EP1406656A2 - VERFAHREN ZUR VERABREICHUNG VON ANTI-TNF$g(a)-ANTIKÖRPERN - Google Patents

VERFAHREN ZUR VERABREICHUNG VON ANTI-TNF$g(a)-ANTIKÖRPERN

Info

Publication number
EP1406656A2
EP1406656A2 EP02741849A EP02741849A EP1406656A2 EP 1406656 A2 EP1406656 A2 EP 1406656A2 EP 02741849 A EP02741849 A EP 02741849A EP 02741849 A EP02741849 A EP 02741849A EP 1406656 A2 EP1406656 A2 EP 1406656A2
Authority
EP
European Patent Office
Prior art keywords
antibody
seq
human
tnfα
antigen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP02741849A
Other languages
English (en)
French (fr)
Other versions
EP1406656B1 (de
EP1406656A4 (de
Inventor
Joachim Kempeni
Roberta Weiss
Steven A. Fischkoff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Biotechnology Ltd
Original Assignee
Abbott Biotech Ltd Bermuda
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23144283&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1406656(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to SI200231020T priority Critical patent/SI1406656T1/sl
Priority to EP10182554A priority patent/EP2359855A3/de
Priority to EP10182602A priority patent/EP2364731A3/de
Priority to EP16198524.7A priority patent/EP3190124A1/de
Priority to EP15165133.8A priority patent/EP2940044B8/de
Priority to EP10181478A priority patent/EP2324851A1/de
Application filed by Abbott Biotech Ltd Bermuda filed Critical Abbott Biotech Ltd Bermuda
Publication of EP1406656A2 publication Critical patent/EP1406656A2/de
Publication of EP1406656A4 publication Critical patent/EP1406656A4/de
Publication of EP1406656B1 publication Critical patent/EP1406656B1/de
Application granted granted Critical
Priority to CY20131100199T priority patent/CY1113774T1/el
Priority to CY20171100183T priority patent/CY1120540T1/el
Anticipated expiration legal-status Critical
Revoked legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/28—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Tumor necrosis factor ⁇ is a cytokine produced by numerous cell types, including monocytes and macrophages, that was originally identified based on its capacity to induce the necrosis of certain mouse tumors (see e.g., Old, L. (1985) Science 230:630-632). Subsequently, a factor termed cachectin, associated with cachexia, was shown to be the same molecule as TNF ⁇ . TNF ⁇ has been implicated in mediating shock (see e.g., Beutler, B. and Cerami, A. (1988) Annu. Rev. Biochem. 57:505-518; Beutler, B. and Cerami, A. (1989) ATOM. Rev. Immunol.
  • TNF ⁇ has been implicated in the pathophysiology of a variety of other human diseases and disorders, including sepsis, infections, autoimmune diseases, transplant rejection and graft-versus-host disease (see e.g., Vasilli, P. (1992) Annu. Rev. Immunol. 10:411-452; Tracey, K.J. and Cerami, A. (1994) Annu. Rev. Med. 45:491- 503).
  • hTNF ⁇ human TNF ⁇
  • therapeutic strategies have been designed to inhibit or counteract hTNF ⁇ activity.
  • mAbs mouse monoclonal antibodies
  • mouse anti-hTNF ⁇ antibodies often displayed high affinity for hTNF ⁇ (e.g., Kd ⁇ 10' ⁇ M) and were able to neutralize hTNF ⁇ activity
  • their use in vivo may be limited by problems associated with administration of mouse antibodies to humans, such as short serum half life, an inability to trigger certain human effector functions and elicitation of an unwanted immune response against the mouse antibody in a human (the "human anti- mouse antibody” (HAMA) reaction).
  • HAMA human anti- mouse antibody
  • murine anti-hTNF ⁇ antibodies have been genetically engineered to be more "human-like.”
  • chimeric antibodies in which the variable regions of the antibody chains are murine-derived and the constant regions of the antibody chains are human-derived, have been prepared (Knight, D.M, et al. (1993) Mol. Immunol. 30:1443- 1453; PCT Publication No. WO 92/16553 by Daddona, P.E., et al).
  • humanized antibodies in which the hypervariable domains of the antibody variable regions are murine-derived but the remainder of the variable regions and the antibody constant regions are human-derived, have also been prepared (PCT Publication No.
  • HACA human anti- chimeric antibody
  • a preferred hTNF ⁇ inhibitory agent to murine mAbs or derivatives thereof would be an entirely human anti-hTNF ⁇ antibody, since such an agent should not elicit the HAMA reaction, even if used for prolonged periods.
  • Human monoclonal autoantibodies against hTNF ⁇ have been prepared using human hybridoma techniques (Boyle, P., et al. (1993) Cell. Immunol. 152:556-568; Boyle, P., et al. (1993) Cell. Immunol. 152:569-581; European Patent Application Publication No. 614 984 A2 by Boyle, et al).
  • hTNF ⁇ antibody Alternative to naturally-occurring human anti-hTNF ⁇ antibodies would be a recombinant hTNF ⁇ antibody.
  • Recombinant human antibodies that bind hTNF ⁇ with relatively low affinity (i.e., K ⁇ ⁇ 10" ⁇ M) and a fast off rate (i.e., K 0 ff ⁇ 10 ⁇ 2 sec 1 ) have been described (Griffiths, A.D., et al. (1993) EMBO J. 12:725-734). However, because of their relatively fast dissociation kinetics, these antibodies may not be suitable for therapeutic use.
  • the present invention provides methods for biweekly dosing regimens for the treatment of TNF ⁇ associated disorders, preferably via a subcutaneous route.
  • Biweekly dosing has many advantages over weekly dosing including, but not limited to, a lower number of total injections, decreased number of injection site reactions (e.g., local pain and swelling), increased patient compliance (i.e., due to less frequent injections), and less cost to the patient as well as the health care provider.
  • Subcutaneous dosing is advantageous because the patient may self-administer a therapeutic substance, e.g., a human TNF ⁇ antibody, which is convenient for both the patient and the health care provider.
  • This invention provides methods for treating disorders in which TNF ⁇ activity is detrimental.
  • the methods include administering biweekly, subcutaneous injections of antibodies to a subject.
  • the antibodies preferably are recombinant human antibodies that specifically bind to human TNF ⁇ .
  • This invention further provides methods for treating disorders in which TNF ⁇ activity is detrimental. These methods include utilizing a combination therapy wherein human antibodies are administered to a subject with another therapeutic agent, such as one or more additional antibodies that bind other targets (e.g., antibodies that bind other cytokines or that bind cell surface molecules), one or more cytokines, soluble TNF ⁇ receptor (see e.g., PCT Publication No.
  • the antibodies are preferably recombinant human antibodies that specifically bind to human TNF ⁇ .
  • the antibodies of the invention are characterized by binding to hTNF ⁇ with high affinity and slow dissociation kinetics and by neutralizing hTNF ⁇ activity, including hTNF ⁇ -induced cytotoxicity (in vitro and in vivo) and hTNF ⁇ -induced cellular activation.
  • the antibodies can be full-length (e.g., an IgGl or IgG4 antibody) or can comprise only an antigen-binding portion (e.g., a Fab, F(ab')2 > scFv fragment or single domain).
  • the most preferred recombinant antibody of the invention termed D2E7, has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3 and a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4 (set forth in Appendix B).
  • the D2E7 antibody has a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2.
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • the invention provides methods of treating disorders in which TNF ⁇ activity is detrimental. These methods include inhibiting human TNF ⁇ activity by subcutaneous, biweekly administration of an anti-TNF ⁇ antibody such that the disorder is treated.
  • the disorder can be, for example, sepsis, an autoimmune disease (e.g., rheumatoid arthritis, allergy, multiple sclerosis, autoimmune diabetes, autoimmune uveitis and nephrotic syndrome), an infectious disease, a malignancy, transplant rejection or graft-versus-host disease, a pulmonary disorder, a bone disorder, an intestinal disorder or a cardiac disorder.
  • an autoimmune disease e.g., rheumatoid arthritis, allergy, multiple sclerosis, autoimmune diabetes, autoimmune uveitis and nephrotic syndrome
  • infectious disease e.g., a malignancy, transplant rejection or graft-versus-host disease
  • a pulmonary disorder e.g., rheumatoid arthritis, allergy, multiple s
  • the invention provides methods of treating disorders in which TNF ⁇ activity is detrimental. These methods include inhibiting human TNF ⁇ activity by subcutaneous administration of an anti-TNF ⁇ antibody and methotrexate such that the disorder is treated.
  • methotrexate is administered together with an anti-TNF ⁇ antibody.
  • methotrexate is administered prior to the administration of an anti-TNF ⁇ antibody.
  • methotrexate is administered subsequent to the administration of an anti-TNF ⁇ antibody.
  • the anti-TNF ⁇ antibody used to treat disorders in which
  • TNF ⁇ activity is detrimental is a human anti-TNF ⁇ antibody.
  • treatment occurs by the biweekly, subcutaneous administration of an isolated human antibody, or an antigen-binding portion thereof.
  • the antibody or antigen-binding portion thereof preferably dissociates from human TNF ⁇ with a K ⁇ of 1 x 10" ⁇ M or less and a K 0 ff rate constant of 1 x 10 ⁇ 3 s ⁇ l or less, both determined by surface plasmon resonance, and neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC50 of 1 x 10 ⁇ M or less.
  • the isolated human antibody, or antigen-binding portion thereof dissociates from human TNF ⁇ with a K 0 ff of 5 x 10 ⁇ 4 s ⁇ l or less, or even more preferably, with a K 0 ff of 1 x 10 ⁇ 4 s ⁇ l or less. More preferably, the isolated human antibody, or antigen-binding portion thereof, neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC50 of 1 x 10" ⁇ M or less, even more preferably with an IC50 of 1 x 10 " 9 M or less and still more preferably with an IC50 of 1 x 10" ⁇ M or less.
  • the invention provides methods of treating disorders in which TNF ⁇ activity is detrimental by the biweekly, subcutaneous administration to the subject a human antibody, or antigen-binding portion thereof.
  • the antibody or antigen-binding portion thereof preferably has the following characteristics: a) dissociates from human TNF ⁇ with a K 0 ff of 1 x 10 ⁇ 3 s"l or less, as determined by surface plasmon resonance; b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9; c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10,
  • the antibody, or antigen-binding portion thereof dissociates from human TNF ⁇ with a K 0 ff of 5 x 10 ⁇ 4 s ⁇ l or less. Still more preferably, the antibody, or antigen-binding portion thereof, dissociates from human TNF ⁇ with a K 0 ff of 1 x 10 ⁇ 4 s ⁇ l or less.
  • the invention provides methods of treating disorders in which TNF ⁇ activity is detrimental. These methods include a biweekly, subcutaneous administration to the subject a human antibody, or an antigen-binding portion thereof.
  • the antibody or antigen-binding portion thereof preferably contains an LCVR having CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, and with an HCVR having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11.
  • the LCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5 and the HCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6. Still more preferably, the LCVR further has CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7 and the HCVR has a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 8.
  • the invention provides methods of treating disorders in which TNF ⁇ activity is detrimental by subcutaneously administering to the subject, biweekly, an isolated human antibody, or an antigen binding portion thereof.
  • the antibody or antigen- binding portion thereof preferably contains an LCVR comprising the amino acid sequence of SEQ ID NO: 1 and an HCVR comprising the amino acid sequence of SEQ ID NO: 2.
  • the antibody has an IgGl heavy chain constant region or an IgG4 heavy chain constant region.
  • the antibody is a Fab fragment, an F(ab')2 fragment or a single chain Fv fragment.
  • the invention provides methods of treating disorders in which the administration of an anti-TNF ⁇ antibody is beneficial by subcutaneously administering to the subject, biweekly, one or more anti-TNF ⁇ antibodies, or antigen-binding portions thereof.
  • the antibody or antigen-binding portion thereof preferably contains an LCVR having CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or with an HCVR having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ
  • kits containing a formulation comprising a pharmaceutical composition comprise an anti-TNF ⁇ antibody and a pharmaceutically acceptable carrier.
  • the kits contain instructions for biweekly subcutaneous dosing of the pharmaceutical composition for the treatment of a disorder in which the administration of an anti-TNF ⁇ antibody is beneficial.
  • the invention pertains to kits containing a formulation comprising a pharmaceutical composition, further comprising an anti-TNF ⁇ antibody, methotrexate, and a pharmaceutically acceptable carrier.
  • the kits contain instructions for subcutaneous dosing of the pharmaceutical composition for the treatment of a disorder in which the administration of an anti-TNF ⁇ antibody is beneficial.
  • Still another aspect of the invention provides a preloaded syringe containing a pharmaceutical composition comprising an anti-TNF ⁇ antibody and a pharmaceutically acceptable carrier.
  • the invention provides a preloaded syringe containing a pharmaceutical composition comprising an anti-TNF ⁇ antibody, methotrexate, and a pharmaceutically acceptable carrier.
  • Figures I A and IB depict the American College of Rheumatology 20 (ACR20) and ACR50 responses for patients suffering from rheumatoid arthritis (RA) after subcutaneous dosing with the antibody D2E7 every week for a total of twelve weeks (1 A), or subcutaneous dosing with the antibody D2E7 and methotrexate every other week (IB) for a total of twenty- four weeks. These data indicate that every other week dosing is as effective as every week dosing.
  • Figure 2 depicts ACR20, ACR50, and ACR70 responses for patients suffering from
  • Figures 3 A and SB depict time courses of tender joint count (3 A) and swollen joint count (3B) over twenty-four weeks for patients suffering from RA after subcutaneous dosing with D2E7 and methotrexate every other week at twenty-four weeks.
  • Figure 4 depicts results from a short form health survey (SF-36) from patients suffering from RA after subcutaneous dosing with the antibody D2E7 and methotrexate every other week at twenty-four weeks.
  • RP role physical
  • PF physical function
  • BP bodily pain
  • GH general health
  • V vitality
  • SF social functioning
  • RE role emotional
  • ME mental health
  • Figure 5 depicts the percentage of ACR responders following a single intravenous injection of the antibody D2E7 and methotrexate in patients suffering from RA.
  • This invention pertains to methods of treating disorders in which the administration of an anti-TNF ⁇ antibody is beneficial comprising the administration of isolated human antibodies, or antigen-binding portions thereof, that bind to human TNF ⁇ with high affinity, a low off rate and high neutralizing capacity such that the disorder is treated.
  • Various aspects of the invention relate to treatment with antibodies and antibody fragments, and pharmaceutical compositions thereof.
  • treating refers to the administration of a substance (e.g., an anti-TNF ⁇ antibody) to achieve a therapeutic objective (e.g., the treatment of a TNF ⁇ - associated disorder).
  • a substance e.g., an anti-TNF ⁇ antibody
  • a therapeutic objective e.g., the treatment of a TNF ⁇ - associated disorder
  • biweekly dosing regimen refers to the time course of administering a substance (e.g., an anti-TNF ⁇ antibody) to a subject to achieve a therapeutic objective (e.g., the treatment of a TNF ⁇ -associated disorder).
  • the biweekly dosing regimen is not intended to include a weekly dosing regimen.
  • the substance is administered every 9-19 days, more preferably, every 11-17 days, even more preferably, every 13-15 days, and most preferably, every 14 days.
  • combination therapy refers to the administration of two or more therapeutic substances, e.g., an anti-TNF ⁇ antibody and the drug methotrexate.
  • the methotrexate may be administered concomitant with, prior to, or following the administration of an anti-TNF ⁇ antibody.
  • human TNF ⁇ (abbreviated herein as hTNF ⁇ , or simply hTNF), as used herein, is intended to refer to a human cytokine that exists as a 17 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer of noncovalently bound 17 kD molecules.
  • the structure of TNF ⁇ is described further in, for example, Pennica, D., et al. (1984) Nature 312:724-729; Davis, J.M., et al (1987) Biochemistry 26:1322-1326; and Jones, E.Y., et al. (1989) Nature 338:225-228.
  • the term human TNF ⁇ is intended to include recombinant human TNF ⁇ (rhTNF ⁇ ), which can be prepared by standard recombinant expression methods or purchased commercially (R & D Systems, Catalog No. 210-TA, Minneapolis, MN).
  • antibody is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CHI, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • antigen-binding portion of an antibody (or simply “antibody portion”), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., hTNF ⁇ ).
  • binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al.
  • VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883) .
  • scFv single chain Fv
  • single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody.
  • Other forms of single chain antibodies, such as diabodies are also encompassed.
  • Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R.J., et al. (1994) Structure 2:1121- 1123).
  • an antibody or antigen-binding portion thereof may be part of a larger immunoadhesion molecules, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides.
  • immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S.M., et al. (1995) Human Antibodies and Hybridomas 6:93- 101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov, S.M., et al.
  • Antibody portions such as Fab and F(ab')2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies.
  • antibodies, antibody portions and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein.
  • human antibody is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.
  • human antibody as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further in Section ⁇ , below), antibodies isolated from a recombinant, combinatorial human antibody library (described further in Section HI, below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor, L.D., et al. (1992) Nucl. Acids Res.
  • Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • an "isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hTNF ⁇ is substantially free of antibodies that specifically bind antigens other than hTNF ⁇ ).
  • An isolated antibody that specifically binds hTNF ⁇ may, however, have cross-reactivity to other antigens, such as hTNF ⁇ molecules from other species (discussed in further detail below).
  • an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • a “neutralizing antibody”, as used herein (or an “antibody that neutralized hTNF ⁇ activity”), is intended to refer to an antibody whose binding to hTNF ⁇ results in inhibition of the biological activity of hTNF ⁇ .
  • This inhibition of the biological activity of hTNF ⁇ can be assessed by measuring one or more indicators of hTNF ⁇ biological activity, such as hTNF ⁇ - induced cytotoxicity (either in vitro or in vivo), hTNF ⁇ -induced cellular activation and hTNF ⁇ binding to hTNF ⁇ receptors.
  • indicators of hTNF ⁇ biological activity can be assessed by one or more of several standard in vitro or in vivo assays known in the art (see
  • Example 4 Preferably, the ability of an antibody to neutralize hTNF ⁇ activity is assessed by inhibition of hTNF ⁇ -induced cytotoxicity of L929 cells.
  • hTNF ⁇ activity the ability of an antibody to inhibit hTNF ⁇ -induced expression of ELAM-1 on HUVEC, as a measure of hTNF ⁇ -induced cellular activation, can be assessed.
  • surface plasmon resonance refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ).
  • K 0 ff is intended to refer to the off rate constant for dissociation of an antibody from the antibody/antigen complex.
  • K ⁇ is intended to refer to the dissociation constant of a particular antibody-antigen interaction.
  • nucleic acid molecule is intended to include DNA molecules and RNA molecules.
  • a nucleic acid molecule may be single-stranded or double- stranded, but preferably is double-stranded DNA.
  • isolated nucleic acid molecule as used herein in reference to nucleic acids encoding antibodies or antibody portions (e.g., VH, VL, CDR3) that bind hTNF ⁇ , is intended to refer to a nucleic acid molecule in which the nucleotide sequences encoding the antibody or antibody portion are free of other nucleotide sequences encoding antibodies or antibody portions that bind antigens other than hTNF ⁇ , which other sequences may naturally flank the nucleic acid in human genomic DNA.
  • an isolated nucleic acid of the invention encoding a VH region of an anti-hTNF ⁇ antibody contains no other sequences encoding other VH regions that bind antigens other than hTNF ⁇ .
  • vector is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • plasmid refers to a circular double stranded DNA loop into which additional DNA segments may be ligated.
  • viral vector Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome.
  • Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors).
  • vectors e.g., non- episomal mammalian vectors
  • vectors can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome.
  • certain vectors are capable of directing the expression of genes to which they are operatively linked.
  • Such vectors are referred to herein as "recombinant expression vectors” (or simply, “expression vectors”).
  • expression vectors of utility in recombinant DNA techniques are often in the form of plasmids.
  • plasmid and vector may be used interchangeably as the plasmid is the most commonly used form of vector.
  • the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno- associated viruses), which serve equivalent functions.
  • viral vectors e.g., replication defective retroviruses, adenoviruses and adeno- associated viruses
  • recombinant host cell (or simply "host cell), as used herein, is intended to refer to a cell into which a recombinant expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” as used herein.
  • This invention provides methods of treating disorders in which the administration of an anti-TNF ⁇ antibody is beneficial. These methods include the biweekly, subcutaneous administration of isolated human antibodies, or antigen-binding portions thereof, that bind to human TNF ⁇ with high affinity, a low off rate and high neutralizing capacity.
  • the human antibodies of the invention are recombinant, neutralizing human anti-hTNF ⁇ antibodies.
  • the most preferred recombinant, neutralizing antibody of the invention is referred to herein as D2E7 (the amino acid sequence of the D2E7 VL region is shown in SEQ ID NO: 1; the amino acid sequence of the D2E7 VH region is shown in SEQ ID NO: 2).
  • D2E7 the amino acid sequence of the D2E7 VL region is shown in SEQ ID NO: 1; the amino acid sequence of the D2E7 VH region is shown in SEQ ID NO: 2.
  • the properties of D2E7 have been described in Salfeld et al, U.S. patent No. 6,090,38
  • the invention pertains to treating disorders in which the administration of an anti-TNF ⁇ antibody is beneficial.
  • treatments include the biweekly, subcutaneous administration of D2E7 antibodies and antibody portions, D2E7 -related antibodies and antibody portions, and other human antibodies and antibody portions with equivalent properties to D2E7, such as high affinity binding to hTNF ⁇ with low dissociation kinetics and high neutralizing capacity.
  • the invention provides treatment with an isolated human antibody, or an antigen-binding portion thereof, that dissociates from human TNF ⁇ with a K ⁇ of 1 x 10 " ⁇ M or less and a K 0 ff rate constant of 1 x 10 ⁇ 3 s ⁇ l or less, both determined by surface plasmon resonance, and neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC50 of 1 x 10 " 7 M or less.
  • the isolated human antibody, or antigen-binding portion thereof dissociates from human TNF ⁇ with a K 0 ff of 5 x 10 ⁇ 4 s ⁇ l or less, or even more preferably, with a K 0 ff of 1 x 10 ⁇ 4 s ⁇ l or less. More preferably, the isolated human antibody, or antigen-binding portion thereof, neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC50 of 1 x 10"8 M or less, even more preferably with an IC50 of 1 x 10 ⁇ 9 M or less and still more preferably with an IC50 of 1 x 10 ⁇ 10 M or less.
  • the antibody is an isolated human recombinant antibody, or an antigen-binding portion thereof. It is well known in the art that antibody heavy and light chain CDR3 domains play an important role in the binding specificity/affinity of an antibody for an antigen. Accordingly, in another aspect, the invention pertains to methods of treating disorders in which the administration of an anti-TNF ⁇ antibody is beneficial by subcutaneous administration of human antibodies that have slow dissociation kinetics for association with hTNF ⁇ and that have light and heavy chain CDR3 domains that structurally are identical to or related to those of D2E7. Position 9 of the D2E7 VL CDR3 can be occupied by Ala or Thr without substantially affecting the K 0 ff.
  • a consensus motif for the D2E7 VL CDR3 comprises the amino acid sequence: Q-R-Y-N-R-A-P-Y-(T/A) (SEQ ID NO: 3). Additionally, position 12 of the D2E7 VH CDR3 can be occupied by Tyr or Asn, without substantially affecting the K 0 ff. Accordingly, a consensus motif for the D2E7 VH CDR3 comprises the amino acid sequence: V-S-Y-L-S-T-A-S-S-L-D-(Y/N) (SEQ ID NO: 4).
  • the CDR3 domain of the D2E7 heavy and light chains is amenable to substitution with a single alanine residue (at position 1, 4, 5, 7 or 8 within the VL CDR3 or at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 within the VH CDR3) without substantially affecting the K 0 ff.
  • substitution of other amino acids within the CDR3 domains may be possible while still retaining the low off rate constant of the antibody, in particular substitutions with conservative amino acids.
  • a “conservative amino acid substitution”, as used herein, is one in which one amino acid residue is replaced with another amino acid residue having a similar side chain.
  • Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
  • no more than one to five conservative amino acid substitutions are made within the D2E7 VL and/or VH CDR3 domains. More preferably, no more than one to three conservative amino acid substitutions are made within the D2E7 VL and or VH CDR3 domains. Additionally, conservative amino acid substitutions should not be made at amino acid positions critical for binding to hTNF ⁇ . Positions 2 and 5 of the D2E7 VL CDR3 and positions 1 and 7 of the D2E7 VH CDR3 appear to be critical for interaction with hTNF ⁇ and thus, conservative amino acid substitutions preferably are not made at these positions (although an alanine substitution at position 5 of the D2E7 VL CDR3 is acceptable, as described above) (see U.S. Patent No. 6,090,382).
  • the invention provides methods of treating disorders in which the administration of an anti-TNF ⁇ antibody is beneficial by the biweekly, subcutaneous administration of an isolated human antibody, or antigen-binding portion thereof.
  • the antibody or antigen-binding portion thereof preferably contains the following characteristics: a) dissociates from human TNF ⁇ with a K 0 ff rate constant of 1 x 10 ⁇ 3 s ⁇ or less, as determined by surface plasmon resonance; b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID
  • SEQ ID NO: 3 or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;
  • c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
  • the antibody, or antigen-binding portion thereof dissociates from human TNF ⁇ with a K 0 ff of 5 x 10 ⁇ 4 s ⁇ l or less. Even more preferably, the antibody, or antigen-binding portion thereof, dissociates from human TNF ⁇ with a K ⁇ ff of 1 x 10 ⁇ 4 s ⁇ l or less.
  • the invention provides methods of treating disorders in which the administration of an anti-TNF ⁇ antibody is beneficial by the biweekly, subcutaneous administration of an isolated human antibody, or an antigen-binding portion thereof.
  • the antibody or antigen-binding portion thereof preferably contains a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, and with a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11.
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • the LCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5 (i.e., the D2E7 VL CDR2) and the HCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6 (i.e., the D2E7 VH CDR2).
  • the LCVR further has CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7 (i.e., the D2E7 VL CDR1) and the HCVR has a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 8 (i.e., the D2E7 VH CDR1).
  • the framework regions for VL preferably are from the V K I human germline family, more preferably from the A20 human germline Vk gene and most preferably from the D2E7 VL framework sequences shown in Figures 1A and IB of U.S. Patent No. 6,090,382.
  • the framework regions for VH preferably are from the VJJ3 human germline family, more preferably from the DP-31 human germline VH gene and most preferably from the D2E7 VH framework sequences shown in Figures 2A and 2B U.S. Patent No. 6,090,382.
  • the invention provides methods of treating disorders in which the administration of an anti-TNF ⁇ antibody is beneficial by the biweekly, subcutaneous administration of an isolated human antibody, or an antigen binding portion thereof.
  • the antibody or antigen-binding portion thereof preferably contains a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 (i.e., the D2E7 VL) and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 (i.e., the D2E7 VH).
  • the antibody comprises a heavy chain constant region, such as an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region.
  • the heavy chain constant region is an IgGl heavy chain constant region or an IgG4 heavy chain constant region.
  • the antibody can comprise a light chain constant region, either a kappa light chain constant region or a lambda light chain constant region.
  • the antibody comprises a kappa light chain constant region.
  • the antibody portion can be, for example, a Fab fragment or a single chain Fv fragment.
  • the invention provides methods of treating disorders in which the administration of an anti-TNF ⁇ antibody is beneficial by the biweekly, subcutaneous administration of an isolated human antibody, or an antigen-binding portions thereof.
  • the antibody or antigen-binding portion thereof preferably contains D2E7 -related VL and VH CDR3 domains, for example, antibodies, or antigen-binding portions thereof, with a light chain variable region (LCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25 and SEQ JD NO: 26 or with a heavy chain variable region (HCVR) having a CDR3 domain comprising an amino acid sequence selected
  • an antibody or antibody portion of the invention can be derivatized or linked to another functional molecule (e.g., another peptide or protein). Accordingly, the antibodies and antibody portions of the invention are intended to include derivatized and otherwise modified forms of the human anti-hTNF ⁇ antibodies described herein, including immunoadhesion molecules.
  • an antibody or antibody portion of the invention can be functionally linked (by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or a diabody), a detectable agent, a cytotoxic agent, a pharmaceutical agent, and/or a protein or peptide that can mediate associate of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).
  • another antibody e.g., a bispecific antibody or a diabody
  • a detectable agent e.g., a cytotoxic agent, a pharmaceutical agent, and/or a protein or peptide that can mediate associate of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).
  • One type of derivatized antibody is produced by crosslinking two or more antibodies (of the same type or of different types, e.g., to create bispecific antibodies).
  • Suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (e.g., m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl suberate).
  • Such linkers are available from Pierce Chemical Company, Rockford, IL.
  • Useful detectable agents with which an antibody or antibody portion of the invention may be derivatized include fluorescent compounds.
  • Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-l- napthalenesulfonyl chloride, phycoerythrin and the like.
  • An antibody may also be derivatized with detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, glucose oxidase and the like. When an antibody is derivatized with a detectable enzyme, it is detected by adding additional reagents that the enzyme uses to produce a detectable reaction product.
  • the detectable agent horseradish peroxidase when the detectable agent horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine leads to a colored reaction product, which is detectable.
  • An antibody may also be derivatized with biotin, and detected through indirect measurement of avidin or streptavidin binding.
  • An antibody, or antibody portion, of the invention can be prepared by recombinant expression of immunoglobulin light and heavy chain genes in a host cell.
  • a host cell is transfected with one or more recombinant expression vectors carrying DNA fragments encoding the immunoglobulin light and heavy chains of the antibody such that the light and heavy chains are expressed in the host cell and, preferably, secreted into the medium in which the host cells are cultured, from which medium the antibodies can be recovered.
  • Standard recombinant DNA methodologies are used to obtain antibody heavy and light chain genes, incorporate these genes into recombinant expression vectors and introduce the vectors into host cells, such as those described in Sambrook, Fritsch and Maniatis (eds), Molecular Cloning; A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y., (1989), Ausubel, F.M. et al. (eds.) Current Protocols in Molecular Biology, Greene Publishing Associates, (1989) and in U.S. Patent No. 4,816,397 by Boss et al
  • DNA fragments encoding the light and heavy chain variable regions are first obtained. These DNAs can be obtained by amplification and modification of germline light and heavy chain variable sequences using the polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • Germline DNA sequences for human heavy and light chain variable region genes are known in the art (see e.g., the "Vbase” human germline sequence database; see also Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NTH Publication No. 91-3242; Tomlinson, I.M., et al.
  • a member of the VJJ3 family of human germline VH genes is amplified by standard PCR. Most preferably, the DP-31 VH germline sequence is amplified.
  • a member of the V K I family of human germline VL genes is amplified by standard PCR. Most preferably, the A20 VL germline sequence is amplified.
  • PCR primers suitable for use in amplifying the DP-31 germline VH and A20 germline VL sequences can be designed based on the nucleotide sequences disclosed in the references cited supra, using standard methods. Once the germline VH and VL fragments are obtained, these sequences can be mutated to encode the D2E7 or D2E7 -related amino acid sequences disclosed herein. The amino acid sequences encoded by the germline VH and VL DNA sequences are first compared to the D2E7 or D2E7 -related VH and VL amino acid sequences to identify amino acid residues in the D2E7 or D2E7 -related sequence that differ from germline.
  • the appropriate nucleotides of the germline DNA sequences are mutated such that the mutated germline sequence encodes the D2E7 or D2E7 -related amino acid sequence, using the genetic code to determine which nucleotide changes should be made.
  • Mutagenesis of the germline sequences is carried out by standard methods, such as PCR-mediated mutagenesis (in which the mutated nucleotides are incorporated into the PCR primers such that the PCR product contains the mutations) or site-directed mutagenesis.
  • DNA fragments encoding D2E7 or D2E7 -related VH and VL segments are obtained (by amplification and mutagenesis of germline VH and VL genes, as described above), these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene. In these manipulations, a VL- or VH- encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker.
  • operatively linked is intended to mean that the two DNA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
  • the isolated DNA encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding DNA to another DNA molecule encoding heavy chain constant regions (CHI, CH2 and CH3).
  • CHI, CH2 and CH3 DNA molecule encoding heavy chain constant regions
  • the heavy chain constant region can be an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most preferably is an IgGl or IgG4 constant region.
  • the VH-encoding DNA can be operatively linked to another DNA molecule encoding only the heavy chain CHI constant region.
  • the isolated DNA encoding the VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL.
  • the sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NTH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
  • the light chain constant region can be a kappa or lambda constant region, but most preferably is a kappa constant region.
  • the VH- and VL-encoding DNA fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly4-Ser)3, such that the VH and VL sequences can be expressed as a contiguous single- chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al, Nature (1990) 348:552-554).
  • a flexible linker e.g., encoding the amino acid sequence (Gly4-Ser)3
  • DNAs encoding partial or full-length light and heavy chains, obtained as described above, are inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences.
  • operatively linked is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene.
  • the expression vector and expression control sequences are chosen to be compatible with the expression host cell used.
  • the antibody light chain gene and the antibody heavy chain gene can be inserted into separate vector or, more typically, both genes are inserted into the same expression vector.
  • the antibody genes are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present).
  • the expression vector Prior to insertion of the D2E7 or D2E7 -related light or heavy chain sequences, the expression vector may already carry antibody constant region sequences.
  • one approach to converting the D2E7 or D2E7-related VH and VL sequences to full-length antibody genes is to insert them into expression vectors already encoding heavy chain constant and light chain constant regions, respectively, such that the VH segment is operatively linked to the CH segment(s) within the vector and the VL segment is operatively linked to ⁇ the CL segment within the vector.
  • the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell.
  • the antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene.
  • the signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
  • the recombinant expression vectors of the invention carry regulatory sequences that control the expression of the antibody chain genes in a host cell.
  • the term "regulatory sequence” is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes.
  • Such regulatory sequences are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990). It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc.
  • Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV) (such as the CMV promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40 promoter/enhancer), adenovirus, (e.g., the adenovirus major late promoter (AdMLP)) and polyoma.
  • CMV cytomegalovirus
  • SV40 Simian Virus 40
  • AdMLP adenovirus major late promoter
  • the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
  • the selectable marker gene facilitates selection of host cells into which the vector has been introduced (see e.g., U.S. Patents Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al).
  • the selectable marker gene confers resistance to drugs, such as G418, hygromycin or methotrexate, on a host cell into which the vector has been introduced.
  • Preferred selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
  • DHFR dihydrofolate reductase
  • neo gene for G418 selection.
  • the expression vector(s) encoding the heavy and light chains is transfected into a host cell by standard techniques.
  • the various forms of the term "transfection" are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like.
  • Preferred mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr- CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R.J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621), NS0 myeloma cells, COS cells and SP2 cells.
  • Chinese Hamster Ovary CHO cells
  • dhfr- CHO cells described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R.J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621
  • the antibodies When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.
  • Host cells can also be used to produce portions of intact antibodies, such as Fab fragments or scFv molecules. It will be understood that variations on the above procedure are within the scope of the present invention. For example, it may be desirable to transfect a host cell with DNA encoding either the light chain or the heavy chain (but not both) of an antibody of this invention. Recombinant DNA technology may also be used to remove some or all of the DNA encoding either or both of the light and heavy chains that is not necessary for binding to hTNF ⁇ . The molecules expressed from such truncated DNA molecules are also encompassed by the antibodies of the invention.
  • bifunctional antibodies may be produced in which one heavy and one light chain are an antibody of the invention and the other heavy and light chain are specific for an antigen other than hTNF ⁇ by crosslinking an antibody of the invention to a second antibody by standard chemical crosslinking methods.
  • a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain is introduced into dhfr-CHO cells by calcium phosphate-mediated transfection.
  • the antibody heavy and light chain genes are each operatively linked to CMV enhancer/AdMLP promoter regulatory elements to drive high levels of transcription of the genes.
  • the recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification.
  • the selected transformant host cells are culture to allow for expression of the antibody heavy and light chains and intact antibody is recovered from the culture medium.
  • Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells and recover the antibody from the culture medium. HI. Selection of Recombinant Human Antibodies
  • Recombinant human antibodies of the invention in addition to D2E7 or an antigen binding portion thereof, or D2E7 -related antibodies disclosed herein can be isolated by screening of a recombinant combinatorial antibody library, preferably a scFv phage display library, prepared using human VL and VH cDNAs prepared from mRNA derived from human lymphocytes. Methodologies for preparing and screening such libraries are known in the art. In addition to commercially available kits for generating phage display libraries (e.g., the Pharmacia Recombinant Phage Antibody System, catalog no. 27-9400-01; and the Stratagene Sur ZAP ⁇ phage display kit, catalog no.
  • kits for generating phage display libraries e.g., the Pharmacia Recombinant Phage Antibody System, catalog no. 27-9400-01; and the Stratagene Sur ZAP ⁇ phage display kit, catalog no.
  • examples of methods and reagents particularly amenable for use in generating and screening antibody display libraries can be found in, for example, Ladner et al. U.S. Patent No. 5,223,409; Kang et al. PCT Publication No. WO 92/18619; Dower et al. PCT Publication No. WO 91/17271; Winter et al. PCT Publication No. WO 92/20791; Markland et al. PCT Publication No. WO 92/15679; Breitling et al. PCT Publication No. WO 93/01288; McCafferty et al. PCT Publication No. WO 92/01047; Garrard et al. PCT Publication No. WO 92/09690; Fuchs et al. (1991)
  • a murine anti-hTNF ⁇ antibody having high affinity and a low off rate constant for hTNF ⁇ is first used to select human heavy and light chain sequences having similar binding activity toward hTNF ⁇ , using the epitope imprinting methods described in Hoogenboom et al, PCT Publication No. WO 93/06213.
  • the antibody libraries used in this method are preferably scFv libraries prepared and screened as described in McCafferty et al. , PCT Publication No.
  • the scFv antibody libraries preferably are screened using recombinant human TNF ⁇ as the antigen.
  • VL and VH segments of the preferred VL VH pair(s) can be randomly mutated, preferably within the CDR3 region of VH and/or VL, in a process analogous to the in vivo somatic mutation process responsible for affinity maturation of antibodies during a natural immune response.
  • This in vitro affinity maturation can be accomplished by amplifying VH and VL regions using PCR primers complimentary to the VH CDR3 or VL CDR3, respectively, which primers have been "spiked” with a random mixture of the four nucleotide bases at certain positions such that the resultant PCR products encode VH and VL segments into which random mutations have been introduced into the VH and/or VL CDR3 regions.
  • These randomly mutated VH and VL segments can be rescreened for binding to hTNF ⁇ and sequences that exhibit high affinity and a low off rate for hTNF ⁇ binding can be selected.
  • nucleic acid encoding the selected antibody can be recovered from the display package (e.g., from the phage genome) and subcloned into other expression vectors by standard recombinant DNA techniques. If desired, the nucleic acid can be further manipulated to create other antibody forms of the invention (e.g., linked to nucleic acid encoding additional immunoglobulin domains, such as additional constant regions).
  • the DNA encoding the antibody is cloned into a recombinant expression vector and introduced into a mammalian host cells, as described in further detail in Section TJ above.
  • the antibodies and antibody-portions of the invention can be incorporated into pharmaceutical compositions suitable for administration to a subject for the methods described herein, e.g., biweekly, subcutaneous dosing.
  • the pharmaceutical composition comprises an antibody (or antibody portion) of the invention and/or methotrexate and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible and are suitable for administration to a subject for the methods described herein.
  • Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.
  • compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies.
  • the preferred mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular injection.
  • the antibody is administered by subcutaneous injection (e.g., a bi
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
  • Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays abso ⁇ tion, for example, monostearate salts and gelatin.
  • the antibodies and antibody-portions of the present invention can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route/mode of administration is subcutaneous injection. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results.
  • the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a carrier such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyethylene glycol (PEG), polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • an antibody or antibody portion of the invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or inco ⁇ orated directly into the subject's diet.
  • the compounds may be inco ⁇ orated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • To administer a compound of the invention by other than parenteral administration it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
  • Supplementary active compounds can also be inco ⁇ orated into the compositions.
  • an antibody or antibody portion of the invention is coformulated with and/or coadministered with one or more additional therapeutic agents.
  • an anti- hTNF ⁇ antibody or antibody portion of the invention may be coformulated and/or coadministered with methotrexate, one or more additional antibodies that bind other targets (e.g., antibodies that bind other cytokines or that bind cell surface molecules), one or more cytokines, soluble TNF ⁇ receptor (see e.g., PCT Publication No.
  • one or more antibodies of the invention may be used in combination with two or more of the foregoing therapeutic agents.
  • Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies.
  • the use of the antibodies, or antibody portions, of the invention in combination with other therapeutic agents is discussed further in subsection IV.
  • Non-limiting examples of therapeutic agents for rheumatoid arthritis with which an antibody, or antibody portion, of the invention can be combined include the following: non- steroidal anti-inflammatory drug(s) (NSAIDs); cytokine suppressive anti-inflammatory drug(s) (CSAIDs); CDP-571/BAY-10-3356 (humanized anti-TNF ⁇ antibody; Celltech/Bayer); cA2 (chimeric anti-TNF ⁇ antibody; Centocor); 75 kdTNFR-IgG (75 kD TNF receptor-IgG fusion protein; Immunex; see e.g., Arthritis & Rheumatism (1994) Vol. 37, S295; J. Invest. Med. (1996) Vol.
  • NSAIDs non- steroidal anti-inflammatory drug(s)
  • CSAIDs cytokine suppressive anti-inflammatory drug(s)
  • CDP-571/BAY-10-3356 humanized anti-TNF ⁇ antibody; Celltech/Bayer
  • Anti-Tac humanized anti-TL-2R ⁇ ; Protein Design Labs/Roche
  • DL-4 anti-inflammatory cytokine; DNAX Schering
  • IL-10 SCH 52000; recombinant IL-10, anti-inflammatory cytokine; DNAX/Schering
  • IL-4 IL-10 and/or EL-4 agonists (e.g., agonist antibodies)
  • IL-1RA IL-1 receptor antagonist; Synergen/Amgen
  • TNF-bp/s-TNFR soluble TNF binding protein; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S284; Amer. J. Physiol.
  • R973401 phosphodiesterase Type IV inhibitor; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S282); MK-966 (COX-2 Inhibitor; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S81); Iloprost (see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S82); methotrexate; thalidomide (see e.g., Arthritis & Rheumatism (1996) Vol. 39, No.
  • thalidomide- related drugs e.g., Celgen
  • leflunomide anti-inflammatory and cytokine inhibitor; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S131; Inflammation Research (1996) Vol. 45, pp. 103-107
  • tranexamic acid inhibitor of plasminogen activation; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S284)
  • T-614 cytokine inhibitor; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No.
  • Meloxicam non-steroidal anti- inflammatory drug
  • Ibuprofen non-steroidal anti-inflammatory drug
  • Piroxicam non- steroidal anti -inflammatory drug
  • Diclofenac non-steroidal anti-inflammatory drug
  • Indomethacin non-steroidal anti-inflammatory drug
  • Sulfasalazine see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S281)
  • Azathioprine see e.g., Arthritis & Rheumatism (1996) Vol. 39, No.
  • ICE inhibitor inhibitor of the enzyme interleukin-l ⁇ converting enzyme
  • zap-70 and/or lck inhibitor inhibitor of the tyrosine kinase zap-70 or lck
  • VEGF inhibitor and/or VEGF-R inhibitor inhibitos of vascular endothelial cell growth factor or vascular endothelial cell growth factor receptor; inhibitors of angiogenesis
  • corticosteroid anti-inflammatory drugs e.g., SB203580
  • TNF- convertase inhibitors anti-IL-12 antibodies
  • interleukin-11 see e.g., Arthritis & Rheumatism (1996) Vol. 39, No.
  • Non-limiting examples of therapeutic agents for inflammatory bowel disease with which an antibody, or antibody portion, of the invention can be combined include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; DL-l receptor antagonists; anti-TL-l ⁇ monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; CDP-571/BAY-10-3356 (humanized anti-TNF ⁇ antibody; Celltech/Bayer); cA2 (chimeric anti-TNF ⁇ antibody; Centocor); 75 kdTNFR-IgG (75 kD TNF
  • Nonlimiting examples of therapeutic agents for multiple sclerosis with which an antibody, or antibody portion, of the invention can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon- ⁇ la (AvonexTM; Biogen); interferon- ⁇ lb (BetaseronTM; Chiron/Berlex); Copolymer 1 (Cop-1; CopaxoneTM; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; clabribine; CDP-571/BAY-10-3356 (humanized anti-TNF ⁇ antibody; Celltech/Bayer); cA2 (chimeric anti-TNF ⁇ antibody; Centocor); 75 kdTNFR-IgG (75 kD TNF receptor-IgG fusion protein; Immunex; see e.g
  • Nonlimiting examples of therapeutic agents for sepsis with which an antibody, or antibody portion, of the invention can be combined include the following: hypertonic saline solutions; antibiotics; intravenous gamma globulin; continuous hemofiltration; carbapenems (e.g., meropenem); antagonists of cytokines such as TNF ⁇ , E -l ⁇ , IL-6 and/or EL-8; CDP- 571/B AY- 10-3356 (humanized anti-TNF ⁇ antibody; Celltech/Bayer); cA2 (chimeric anti- TNF ⁇ antibody; Centocor); 75 kdTNFR-IgG (75 kD TNF receptor-IgG fusion protein; Immunex; see e.g., Arthritis & Rheumatism (1994) Vol.
  • lisofylline synthetic small molecule methylxan thine; Cell Therapeutics, Inc.
  • PGG-Glucan aqeuous soluble ⁇ l,3glucan; Alpha-Beta Technology
  • apolipoprotein A-l reconstituted with lipids chiral hydroxamic acids (synthetic antibacterials that inhibit lipid A biosynthesis); anti-endotoxin antibodies; E5531 (synthetic lipid A antagonist; Eisai America, Inc.); rBPI 2 ⁇ (recombinant N-terminal fragment of human Bactericidal/Permeability- Increasing Protein); and Synthetic Anti-Endotoxin Peptides (SAEP; BiosYnth Research Laboratories);
  • Nonlimiting examples of therapeutic agents for adult respiratory distress syndrome (ARDS) with which an antibody, or antibody portion, of the invention can be combined include the following: anti-IL-8 antibodies; surfactant replacement therapy; CDP-571/BAY- 10-3356 (humanized anti-TNF ⁇ antibody; Celltech/Bayer); cA2 (chimeric anti-TNF ⁇ antibody; Centocor); 75 kdTNFR-IgG (75 kD TNF receptor-IgG fusion protein; Immunex; see e.g., Arthritis & Rheumatism (1994) Vol. 37, S295; J. Invest. Med. (1996) Vol.
  • compositions of the invention may include a "therapeutically effective amount” or a “prophylactically effective amount” of an antibody or antibody portion of the invention.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the antibody or antibody portion may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of an antibody or antibody portion of the invention is 10-100 mg, more preferably 20- 80 mg and most preferably about 40 mg. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the anti-hTNF ⁇ antibodies, or portions thereof, of the invention can be used to detect hTNF ⁇ (e.g., in a biological sample, such as serum or plasma), using a conventional immunoassay, such as an enzyme linked immunosorbent assays (ELISA), an radioimmunoassay (RIA) or tissue immunohistochemistry.
  • a conventional immunoassay such as an enzyme linked immunosorbent assays (ELISA), an radioimmunoassay (RIA) or tissue immunohistochemistry.
  • ELISA enzyme linked immunosorbent assays
  • RIA radioimmunoassay
  • tissue immunohistochemistry tissue immunohistochemistry.
  • the invention provides a method for detecting hTNF ⁇ in a biological sample comprising contacting a biological sample with an antibody, or antibody portion, of the invention and detecting either the antibody (or antibody portion) bound to hTNF ⁇ or unbound antibody (or antibody portion), to thereby detect hTNF ⁇ in the biological sample.
  • Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials and radioactive materials.
  • suitable enzymes include horseradish peroxidase, alkaline phosphatase, ⁇ -galactosidase, or acetylcholinesterase
  • suitable prosthetic group complexes include streptavidin/biotin and avidin biotin
  • suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin
  • an example of a luminescent material includes luminol
  • suitable radioactive material include 125 I, 131 I, 35 S or 3 H.
  • hTNF ⁇ can be assayed in biological fluids by a competition immunoassay utilizing rhTNF ⁇ standards labeled with a detectable substance and an unlabeled anti-hTNF ⁇ antibody.
  • the biological sample, the labeled rhTNF ⁇ standards and the anti-hTNF ⁇ antibody are combined and the amount of labeled rhTNF ⁇ standard bound to the unlabeled antibody is determined.
  • the amount of hTNF ⁇ in the biological sample is inversely proportional to the amount of labeled hTNF ⁇ standard bound to the anti-hTNF ⁇ antibody.
  • a D2E7 antibody of the invention can also be used to detect TNF ⁇ s from species other than humans, in particular TNF ⁇ s from primates (e.g., chimpanzee, baboon, marmoset, cynomolgus and rhesus), pig and mouse, since D2E7 can bind to each of these TNF ⁇ s.
  • the antibodies and antibody portions of the invention are capable of neutralizing hTNF ⁇ activity both in vitro and in vivo (see U.S. Patent No. 6,090,382).
  • at least some of the antibodies of the invention, such as D2E7 can neutralize hTNF ⁇ activity from other species.
  • the antibodies and antibody portions of the invention can be used to inhibit hTNF ⁇ activity, e.g., in a cell culture containing hTNF ⁇ , in human subjects or in other mammalian subjects having TNF ⁇ s with which an antibody of the invention cross- reacts (e.g. chimpanzee, baboon, marmoset, cynomolgus and rhesus, pig or mouse).
  • the invention provides a method for inhibiting TNF ⁇ activity comprising contacting TNF ⁇ with an antibody or antibody portion of the invention such that TNF ⁇ activity is inhibited.
  • the TNF ⁇ is human TNF ⁇ .
  • an antibody or antibody portion of the invention can be added to the culture medium to inhibit hTNF ⁇ activity in the culture.
  • the invention provides methods of treating disorders in which the administration of an anti-TNF ⁇ antibody is beneficial, comprising subcutaneously administering to the subject biweekly an antibody or antibody portion of the invention such that the disorder is treated.
  • the antibody is administered subcutaneously on a biweekly schedule.
  • the antibody is administered subcutaneously before, during or after administration of methotrexate.
  • the subject is a human subject.
  • the subject can be a mammal expressing a TNF ⁇ with which an antibody of the invention cross- reacts.
  • the subject can be a mammal into which has been introduced hTNF ⁇ (e.g., by administration of hTNF ⁇ or by expression of an hTNF ⁇ transgene).
  • An antibody of the invention can be administered to a human subject for therapeutic pu ⁇ oses (discussed further below).
  • an antibody of the invention can be administered to a non-human mammal expressing a TNF ⁇ with which the antibody cross-reacts (e.g., a primate, pig or mouse) for veterinary pu ⁇ oses or as an animal model of human disease.
  • a primate, pig or mouse for veterinary pu ⁇ oses or as an animal model of human disease.
  • animal models may be useful for evaluating the therapeutic efficacy of antibodies of the invention (e.g., testing of dosages and time courses of administration).
  • a disorder in which the administration of an anti-TNF ⁇ antibody is beneficial is intended to include diseases and other disorders in which the presence of TNF ⁇ in a subject suffering from the disorder has been shown to be or is suspected of being either responsible for the pathophysiology of the disorder or a factor that contributes to a worsening of the disorder, or where it has been shown that another anti- TNF ⁇ antibody or a biologically active portion thereof has been successfully used to treat the disease. Accordingly, a disorder in which TNF ⁇ activity is detrimental is a disorder in which inhibition of TNF ⁇ activity is expected to alleviate the symptoms and/or progression of the disorder.
  • Such disorders may be evidenced, for example, by an increase in the concentration of TNF ⁇ in a biological fluid of a subject suffering from the disorder (e.g., an increase in the concentration of TNF ⁇ in serum, plasma, synovial fluid, etc. of the subject), which can be detected, for example, using an anti-TNF ⁇ antibody as described above.
  • TNF ⁇ activity is detrimental.
  • the use of the antibodies and antibody portions of the invention in the treatment of specific disorders is discussed further below: A. Sepsis
  • Tumor necrosis factor has an established role in the pathophysiology of sepsis, with biological effects that include hypotension, myocardial suppression, vascular leakage syndrome, organ necrosis, stimulation of the release of toxic secondary mediators and activation of the clotting cascade (see e.g., Tracey, K.J. and Cerami, A. (1994) Annu. Rev. Med. 45:491-503; Russell, D and Thompson, R.C. (1993) Curr. Opin. Biotech. 4:114-121). Accordingly, the human antibodies, and antibody portions, of the invention can be used to treat sepsis in any of its clinical settings, including septic shock, endotoxic shock, gram negative sepsis and toxic shock syndrome.
  • an anti-hTNF ⁇ antibody, or antibody portion, of the invention can be coadministered with one or more additional therapeutic agents that may further alleviate sepsis, such as an interleukin-1 inhibitor (such as those described in PCT Publication Nos. WO 92/16221 and WO 92/17583), the cytokine interleukin-6 (see e.g., PCT Publication No. WO 93/11793) or an antagonist of platelet activating factor (see e.g., European Patent Application Publication No. EP 374 510).
  • an interleukin-1 inhibitor such as those described in PCT Publication Nos. WO 92/16221 and WO 92/17583
  • the cytokine interleukin-6 see e.g., PCT Publication No. WO 93/11793
  • an antagonist of platelet activating factor see e.g., European Patent Application Publication No. EP 374 510.
  • an anti-TNF ⁇ antibody or antibody portion of the invention is administered to a human subject within a subgroup of sepsis patients having a serum or plasma concentration of IL-6 above 500 pg/ml, and more preferably 1000 pg/ml, at the time of treatment (see PCT Publication No. WO 95/20978 by Daum, L., et al).
  • Tumor necrosis factor has been implicated in playing a role in the pathophysiology of a variety of autoimmune diseases.
  • TNF ⁇ has been implicated in activating tissue inflammation and causing joint destruction in rheumatoid arthritis (see e.g., Tracey and Cerami, supra; Arend, W.P. and Dayer, J-M. (1995) Arth. Rheum. 38:151-160; Fava, R.A., et al. (1993) Clin. Exp. Immunol. 94:261-266).
  • TNF ⁇ also has been implicated in promoting the death of islet cells and in mediating insulin resistance in diabetes (see e.g., Tracey and Cerami, supra; PCT Publication No.
  • TNF ⁇ also has been implicated in mediating cytotoxicity to oligodendrocytes and induction of inflammatory plaques in multiple sclerosis (see e.g., Tracey and Cerami, supra).
  • Chimeric and humanized murine anti-hTNF ⁇ antibodies have undergone clinical testing for treatment of rheumatoid arthritis (see e.g.,
  • the human antibodies, and antibody portions of the invention can be used to treat autoimmune diseases, in particular those associated with inflammation, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and gouty arthritis, allergy, multiple sclerosis, autoimmune diabetes, autoimmune uveitis and nephrotic syndrome.
  • the antibody, or antibody portion is administered systemically, although for certain disorders, local administration of the antibody or antibody portion at a site of inflammation may be beneficial (e.g., local administration in the joints in rheumatoid arthritis or topical application to diabetic ulcers, alone or in combination with a cyclohexane-ylidene derivative as described in PCT Publication No. WO 93/19751).
  • Tumor necrosis factor has been implicated in mediating biological effects observed in a variety of infectious diseases.
  • TNF ⁇ has been implicated in mediating brain inflammation and capillary thrombosis and infarction in malaria (see e.g., Tracey and Cerami, supra).
  • TNF ⁇ also has been implicated in mediating brain inflammation, inducing breakdown of the blood-brain barrier, triggering septic shock syndrome and activating venous infarction in meningitis (see e.g., Tracey and Cerami, supra).
  • TNF ⁇ also has been implicated in inducing cachexia, stimulating viral proliferation and mediating central nervous system injury in acquired immune deficiency syndrome (AIDS) (see e.g., Tracey and Cerami, supra).
  • AIDS acquired immune deficiency syndrome
  • the antibodies, and antibody portions, of the invention can be used in the treatment of infectious diseases, including bacterial meningitis (see e.g., European Patent Application Publication No. EP 585 705), cerebral malaria, AIDS and AIDS-related complex (ARC) (see e.g., European Patent Application Publication No. EP 230 574), as well as cytomegalovirus infection secondary to transplantation (see e.g., Fietze, E., et al (1994) Transplantation 58:675-680).
  • infectious diseases including bacterial meningitis (see e.g., European Patent Application Publication No. EP 585 705), cerebral malaria, AIDS and AIDS-related complex (ARC) (see e.g., European Patent Application Publication No. EP 230 574), as well as cytomegalovirus infection secondary to transplantation (see e.g., Fietze, E., et al (1994) Transplantation 58:675-680).
  • Tumor necrosis factor has been implicated as a key mediator of allograft rejection and graft versus host disease (GVHD) and in mediating an adverse reaction that has been observed when the rat antibody OKT3, directed against the T cell receptor CD3 complex, is used to inhibit rejection of renal transplants (see e.g. ,. Tracey and Cerami, supra; Eason, J.D., et al. (1995) Transplantation 59:300-305; Suthanthiran, M. and Strom, T.B. (1994) New Engl. J. Med. 331:365-375).
  • the antibodies, and antibody portions, of the invention can be used to inhibit transplant rejection, including rejections of allografts and xenografts and to inhibit GVHD.
  • the antibody or antibody portion may be used alone, more preferably it is used in combination with one or more other agents that inhibit the immune response against the allograft or inhibit GVHD.
  • an antibody or antibody portion of the invention is used in combination with OKT3 to inhibit OKT3-induced reactions.
  • an antibody or antibody portion of the invention is used in combination with one or more antibodies directed at other targets involved in regulating immune responses, such as the cell surface molecules CD25
  • an antibody or antibody portion of the invention is used in combination with one or more general immunosuppressive agents, such as cyclosporin A or FK506.
  • one or more general immunosuppressive agents such as cyclosporin A or FK506.
  • the antibodies, and antibody portions, of the invention can be used in the treatment of malignancies, to inhibit tumor growth or metastasis and/or to alleviate cachexia secondary to malignancy.
  • the antibody, or antibody portion may be administered systemically or locally to the tumor site.
  • Tumor necrosis factor has been implicated in the pathophysiology of adult respiratory distress syndrome, including stimulating leukocyte-endothelial activation, directing cytotoxicity to pneumocytes and inducing vascular leakage syndrome (see e.g., Tracey and Cerami, supra).
  • the antibodies, and antibody portions, of the invention can be used to treat various pulmonary disorders, including adult respiratory distress syndrome (see e.g., PCT Publication No. WO 91/04054), shock lung, chronic pulmonary inflammatory disease, pulmonary sarcoidosis, pulmonary fibrosis and silicosis.
  • the antibody, or antibody portion may be administered systemically or locally to the lung surface, for example as an aerosol.
  • Tumor necrosis factor has been implicated in the pathophysiology of inflammatory bowel disorders (see e.g., Tracy, K.J., et al (1986) Science 234:470-474; Sun, X-M., et al. (1988) J. Clin. Invest. 81:1328-1331; MacDonald, T.T., et al. (1990) Clin. Exp. Immunol. 81:301-305).
  • Chimeric murine anti-hTNF ⁇ antibodies have undergone clinical testing for treatment of Crohn's disease (van Dullemen, H.M., et al. (1995) Gastroenterology 109:129- 135).
  • the human antibodies, and antibody portions, of the invention also can be used to treat intestinal disorders, such as idiopathic inflammatory bowel disease, which includes two syndromes, Crohn's disease and ulcerative colitis.
  • the antibodies, and antibody portions, of the invention also can be used to treat various cardiac disorders, including ischemia of the heart (see e.g., European Patent Application Publication No. EP 453 898) and heart insufficiency (weakness of the heart muscle) (see e.g., PCT Publication No. WO 94/20139).
  • the antibodies, and antibody portions, of the invention also can be used to treat various other disorders in which TNF ⁇ activity is detrimental.
  • diseases and disorders in which TNF ⁇ activity has been implicated in the pathophysiology include inflammatory bone disorders and bone reso ⁇ tion disease (see e.g., Bertolini, D.R., et al. (1986) Nature 319:516-518; Konig, A., et al. (1988) J. Bone Miner. Res. 3:621-627; Lerner, U.H. and Ohlin, A. (1993) J. Bone Miner. Res. 8:147-155; and Shankar, G. and Stern, P.H.
  • hepatitis including alcoholic hepatitis (see e.g., McClain, C.J. and Cohen, D.A. (1989) Hepatology 9:349-351; Felver, M.E., et al. (1990) Alcohol. Clin. Exp. Res. 14:255-259; and Hansen, J., et al. (1994) Hepatology 20:461-474) and viral hepatitis (Sheron, N., et al. (1991) J. Hepatol. 12:241-245; and Hussain, M.J., et al. (1994) J. Clin. Pathol.
  • Patients participating in this study had a mean duration of disease of 10.1 years with a disease activity score (DAS) score of 4.87 and a mean of 3.4 DMARDs (disease modifying anti-rheumatic drugs) prior to study entry; again reflecting considerable disease activity.
  • DAS disease activity score
  • DMARDs disease modifying anti-rheumatic drugs
  • Demographic characteristics of the study population of this study included a mean duration of RA of 11.1 years, prior exposure to a mean of 3.6 DMARDs (other than MTX), and a mean DAS at study entry of 4.81.
  • a mean duration of RA of 11.1 years
  • a mean of 3.6 DMARDs other than MTX
  • a mean DAS at study entry of 4.81 By Day twenty-nine, 72% of the i.v. D2E7 treated patients and 44% of the s.c. D2E7 treated patients had achieved a response by DAS criteria, compared to only 28% of placebo-treated patients (set forth in Figure 5). Of the responders in this study, 28% of placebo treated patients maintained an ACR20 response up to day 29, compared to 72% of i.v. -treated D2E7 patients and 67% of s.c. -treated D2E7 patients, who maintained their responses for between one and three months.
  • This study enrolled two hundred eighty-four patients with RA and was designed to determine the optimal total body dose of subcutaneously administered D2E7. Patients were randomized to receive either 20, 40, or 80 mg D2E7 or placebo weekly for twelve weeks, after which time placebo-treated patients were switched blindly to 40 mg D2E7/week.
  • EXAMPLE 3 Biweekly, Subcutaneous Administration Of An Anti-TNF ⁇ Antibody Biweekly, Subcutaneous Administration Of D2E7
  • the clinical effects, safety, immunogenicity, and tolerance of RA patients with partial responses to MTX following every other week subcutaneous (s.c.) injections of placebo or D2E7 at several dose levels for up to twenty-four weeks in conjunction with continued MTX treatment was investigated.
  • Study Design A placebo-controlled, double-blind, randomized, multi-center study in patients with
  • RA who had insufficient efficacy or tolerability to MTX was performed.
  • patients were continued on a stable dose of MTX with dose ranges specified in the inclusion criteria described below.
  • This study consisted of two portions: 1) a "wash-out period" of four weeks prior to the administration of the first dose medication, during which time DMARDs (except for MTX) were withdrawn; and 2) a "placebo controlled period" during which time patients were randomized to one of four cohorts of sixty-seven patients to receive placebo, 20, 40, or 80 mg D2E7 (as a total body dose) given every other week s.c. for up to 24 weeks. Each dose of study drug was administered as two s.c.
  • the study population was representative of the moderate to severe RA population in North America: approximately 70% female, and predominantly over the age of forty.
  • the population was selected using predetermined inclusion and exclusion criteria, known to those of skill in the art e.g., a patient must have received a diagnosis of RA as defined by the 1987-revised American College of Rheumatology (ACR) criteria (set forth in Appendix A).
  • ACR American College of Rheumatology
  • Figures IB and 2-4 indicate that subcutaneous, biweekly D2E7 treatment combined with methotrexate was significantly better than placebo in reducing the signs and symptoms of RA at twenty-four weeks. All three doses of D2E7 were statistically significantly more effective than placebo given weekly. Furthermore, D2E7 at 40 mg and 80 mg had better efficacy than the 20 mg dose.
  • a patient is said to have RA if he/she is included in 1 of the SRA subsets listed in able 7 and has a clinical diagnosis of RA by his her physi ⁇ an. Criteria 1 , 2, and 3 must have been present for at least 6 weeks
  • SEQ ID NO: 26 SEQ ID NO : 27 :

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Diabetes (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
EP02741849A 2001-06-08 2002-06-05 Verfahren zur verabreichung von anti-tnf-alpha-antikörpern Revoked EP1406656B1 (de)

Priority Applications (8)

Application Number Priority Date Filing Date Title
SI200231020T SI1406656T1 (sl) 2001-06-08 2002-06-05 Postopek dajanja anti-TNF-alfa protiteles
EP10182554A EP2359855A3 (de) 2001-06-08 2002-06-05 Verfahren zur Verabreichung von Anti-TNFalpha-Antikörpern
EP10182602A EP2364731A3 (de) 2001-06-08 2002-06-05 Verfahren zur Verabreichung von Anti-TNFalpha-Antikörpern
EP16198524.7A EP3190124A1 (de) 2001-06-08 2002-06-05 Adalimumab zur verwendung in der behandlung von rheumatoider arthritis
EP15165133.8A EP2940044B8 (de) 2001-06-08 2002-06-05 Anti-tnf-alpha-antikörpern zur verwendung in therapie
EP10181478A EP2324851A1 (de) 2001-06-08 2002-06-05 Verfahren zur verabreichung von anti-TNFalpha-Antikörpern
CY20131100199T CY1113774T1 (el) 2001-06-08 2013-03-05 ΜΕΘΟΔΟΙ ΧΟΡΗΓΗΣΗΣ ΑΝΤΙΣΩΜΑΤΩΝ ANTI-TNFa
CY20171100183T CY1120540T1 (el) 2001-06-08 2017-02-08 ΜΕΘΟΔΟΙ ΧΟΡΗΓΗΣΗΣ ΑΝΤΙΣΩΜΑΤΩΝ ANTI-TNFa

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US29696101P 2001-06-08 2001-06-08
US296961P 2001-06-08
PCT/US2002/017790 WO2002100330A2 (en) 2001-06-08 2002-06-05 METHODS OF ADMINISTERING ANTI-TNFα ANTIBODIES

Related Child Applications (5)

Application Number Title Priority Date Filing Date
EP15165133.8A Division EP2940044B8 (de) 2001-06-08 2002-06-05 Anti-tnf-alpha-antikörpern zur verwendung in therapie
EP16198524.7A Division EP3190124A1 (de) 2001-06-08 2002-06-05 Adalimumab zur verwendung in der behandlung von rheumatoider arthritis
EP10181478.8 Division-Into 2010-09-28
EP10182554.5 Division-Into 2010-09-29
EP10182602.2 Division-Into 2010-09-29

Publications (3)

Publication Number Publication Date
EP1406656A2 true EP1406656A2 (de) 2004-04-14
EP1406656A4 EP1406656A4 (de) 2006-05-24
EP1406656B1 EP1406656B1 (de) 2013-01-09

Family

ID=23144283

Family Applications (6)

Application Number Title Priority Date Filing Date
EP02741849A Revoked EP1406656B1 (de) 2001-06-08 2002-06-05 Verfahren zur verabreichung von anti-tnf-alpha-antikörpern
EP10181478A Withdrawn EP2324851A1 (de) 2001-06-08 2002-06-05 Verfahren zur verabreichung von anti-TNFalpha-Antikörpern
EP15165133.8A Expired - Lifetime EP2940044B8 (de) 2001-06-08 2002-06-05 Anti-tnf-alpha-antikörpern zur verwendung in therapie
EP16198524.7A Withdrawn EP3190124A1 (de) 2001-06-08 2002-06-05 Adalimumab zur verwendung in der behandlung von rheumatoider arthritis
EP10182554A Withdrawn EP2359855A3 (de) 2001-06-08 2002-06-05 Verfahren zur Verabreichung von Anti-TNFalpha-Antikörpern
EP10182602A Withdrawn EP2364731A3 (de) 2001-06-08 2002-06-05 Verfahren zur Verabreichung von Anti-TNFalpha-Antikörpern

Family Applications After (5)

Application Number Title Priority Date Filing Date
EP10181478A Withdrawn EP2324851A1 (de) 2001-06-08 2002-06-05 Verfahren zur verabreichung von anti-TNFalpha-Antikörpern
EP15165133.8A Expired - Lifetime EP2940044B8 (de) 2001-06-08 2002-06-05 Anti-tnf-alpha-antikörpern zur verwendung in therapie
EP16198524.7A Withdrawn EP3190124A1 (de) 2001-06-08 2002-06-05 Adalimumab zur verwendung in der behandlung von rheumatoider arthritis
EP10182554A Withdrawn EP2359855A3 (de) 2001-06-08 2002-06-05 Verfahren zur Verabreichung von Anti-TNFalpha-Antikörpern
EP10182602A Withdrawn EP2364731A3 (de) 2001-06-08 2002-06-05 Verfahren zur Verabreichung von Anti-TNFalpha-Antikörpern

Country Status (33)

Country Link
US (16) US8889135B2 (de)
EP (6) EP1406656B1 (de)
JP (7) JP2005517629A (de)
KR (8) KR101715028B1 (de)
CN (5) CN105412922A (de)
AR (3) AR034429A1 (de)
AU (1) AU2002314922C1 (de)
BG (2) BG66459B1 (de)
BR (1) BR0206289A (de)
CA (3) CA2868614A1 (de)
CL (1) CL2012000856A1 (de)
CY (1) CY1120540T1 (de)
CZ (1) CZ309160B6 (de)
DK (2) DK2940044T3 (de)
EC (1) ECSP034867A (de)
ES (2) ES2400458T3 (de)
HK (1) HK1065471A1 (de)
HU (1) HU230947B1 (de)
IL (4) IL158831A0 (de)
LT (1) LT2940044T (de)
MX (2) MXPA03011316A (de)
NO (2) NO334490B1 (de)
NZ (6) NZ573478A (de)
PE (2) PE20160999A1 (de)
PH (3) PH12013500297A1 (de)
PL (4) PL217666B1 (de)
PT (2) PT2940044T (de)
SA (1) SA02230384B1 (de)
SI (2) SI1406656T1 (de)
SK (1) SK288509B6 (de)
TW (1) TWI473622B (de)
WO (1) WO2002100330A2 (de)
ZA (1) ZA200308861B (de)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8992926B2 (en) 2001-06-08 2015-03-31 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
US10376582B2 (en) 2013-10-16 2019-08-13 Outlook Therapeutics, Inc. Buffer formulations for enhanced antibody stability
US10653747B2 (en) 2014-07-31 2020-05-19 Uab Research Foundation ApoE mimetic peptides and higher potency to clear plasma cholesterol

Families Citing this family (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6090382A (en) * 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
HU228630B1 (en) 1996-02-09 2013-04-29 Abbott Biotech Ltd Use of human anti bodies that bind human tnf-alpha and process for inhibiting of human tnf-alpha activity
US20030206898A1 (en) * 2002-04-26 2003-11-06 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
US20040009172A1 (en) * 2002-04-26 2004-01-15 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
US20090280065A1 (en) * 2006-04-10 2009-11-12 Willian Mary K Uses and Compositions for Treatment of Psoriasis
MXPA05000815A (es) * 2002-07-19 2005-04-28 Abbott Biotech Ltd Tratamiento de trastornos relacionados con tnfa.
US20040033228A1 (en) 2002-08-16 2004-02-19 Hans-Juergen Krause Formulation of human antibodies for treating TNF-alpha associated disorders
MY150740A (en) * 2002-10-24 2014-02-28 Abbvie Biotechnology Ltd Low dose methods for treating disorders in which tnf? activity is detrimental
WO2004087730A2 (en) * 2003-03-27 2004-10-14 The Johns Hopkins University Method for producing diverse libraries of encoded polymers
US7344716B2 (en) * 2003-05-13 2008-03-18 Depuy Spine, Inc. Transdiscal administration of specific inhibitors of pro-inflammatory cytokines
US8273347B2 (en) * 2003-05-13 2012-09-25 Depuy Spine, Inc. Autologous treatment of degenerated disc with cells
US7892563B2 (en) * 2003-05-20 2011-02-22 Wyeth Holdings Corporation Methods for treatment of severe acute respiratory syndrome (SARS)
US8361467B2 (en) * 2003-07-30 2013-01-29 Depuy Spine, Inc. Trans-capsular administration of high specificity cytokine inhibitors into orthopedic joints
US8895540B2 (en) 2003-11-26 2014-11-25 DePuy Synthes Products, LLC Local intraosseous administration of bone forming agents and anti-resorptive agents, and devices therefor
TW201705980A (zh) 2004-04-09 2017-02-16 艾伯維生物技術有限責任公司 用於治療ＴＮＦα相關失調症之多重可變劑量療法
AU2011218744B2 (en) * 2004-04-09 2012-09-20 Abbvie Biotechnology Ltd Multiple-variable dose regimen for treating TNFalpha-related disorders
GB0414054D0 (en) 2004-06-23 2004-07-28 Owen Mumford Ltd Improvements relating to automatic injection devices
WO2006014477A1 (en) * 2004-07-06 2006-02-09 Bioren, Inc. HIGH AFFINITY ANTI-TNF-α ANTIBODIES AND METHOD
WO2006041970A2 (en) * 2004-10-08 2006-04-20 Abbott Biotechnology Ltd. Treatment of respiratory syncytial virus (rsv) infection
US20060253100A1 (en) 2004-10-22 2006-11-09 Medtronic, Inc. Systems and Methods to Treat Pain Locally
WO2006114115A1 (de) 2005-04-26 2006-11-02 Trion Pharma Gmbh Kombination von antikörpern mit glukokortikoiden zur behandlung von krebs
AU2012254978C1 (en) * 2005-05-16 2017-06-01 Abbvie Biotechnology Ltd Use of TNF inhibitor for treatment of erosive polyarthritis
CN102961746B (zh) 2005-05-16 2016-06-15 艾伯维生物技术有限公司 TNFα抑制剂治疗腐蚀性多关节炎的用途
US20070041905A1 (en) * 2005-08-19 2007-02-22 Hoffman Rebecca S Method of treating depression using a TNF-alpha antibody
BRPI0618085A2 (pt) * 2005-11-01 2011-08-16 Abbott Biotech Ltd processos e kits para diagnóstico de espondilite ancilosante usando biomarcadores
WO2007110219A1 (en) * 2006-03-27 2007-10-04 Ablynx N.V. Medical delivery device for therapeutic proteins based on single domain antibodies
JP5308328B2 (ja) 2006-04-04 2013-10-09 シングレックス，インコーポレイテッド トロポニンの分析のための高感度のシステムおよび方法
CA2911000A1 (en) * 2006-04-05 2007-10-18 Min W. Wan Antibody purification
EP2010214A4 (de) * 2006-04-10 2010-06-16 Abbott Biotech Ltd Verwendung und zusammensetzungen zur behandlung von rheumatoider arthritis
CA2564435A1 (en) 2006-04-10 2007-10-10 Abbott Biotechnology Ltd. Methods for monitoring and treating intestinal disorders
EP2666479A3 (de) 2006-04-10 2014-03-26 Abbott Biotechnology Ltd Anwendungen und Zusammensetzungen zur Behandlung von juveniler rheumatoider Arthritis
US20090317399A1 (en) * 2006-04-10 2009-12-24 Pollack Paul F Uses and compositions for treatment of CROHN'S disease
EP2010213A4 (de) * 2006-04-10 2010-08-11 Abbott Biotech Ltd Verwendung und zusammensetzungen zur behandlung von juveniler rheumatoider arthritis
EP2666472A3 (de) 2006-04-10 2014-04-02 Abbott Biotechnology Ltd Anwendungen und Zusammensetzungen zur Behandlung von Psoriasis-Arthritis
WO2007120626A2 (en) 2006-04-10 2007-10-25 Abbott Biotechnology Ltd. Uses and compositions for treatment of ankylosing spondylitis
US9605064B2 (en) 2006-04-10 2017-03-28 Abbvie Biotechnology Ltd Methods and compositions for treatment of skin disorders
US20080131374A1 (en) * 2006-04-19 2008-06-05 Medich John R Uses and compositions for treatment of rheumatoid arthritis
US20090186047A1 (en) * 2006-04-25 2009-07-23 Intercell Ag HCV Vaccinations
US20080311043A1 (en) * 2006-06-08 2008-12-18 Hoffman Rebecca S Uses and compositions for treatment of psoriatic arthritis
US20100021451A1 (en) 2006-06-08 2010-01-28 Wong Robert L Uses and compositions for treatment of ankylosing spondylitis
JP5535623B2 (ja) 2006-06-30 2014-07-02 アッヴィ バイオテクノロジー リミテッド 自動注射装置
EP2089428B1 (de) * 2006-10-27 2013-11-20 AbbVie Biotechnology Ltd Kristalline anti-htnfalpha-antikörper
EP2679995A1 (de) * 2007-05-31 2014-01-01 AbbVie Inc. Biomarker zur Vorhersage der Reaktion auf TNF-alpha-Hemmer bei Autoimmunerkrankungen
WO2008154543A2 (en) 2007-06-11 2008-12-18 Abbott Biotechnology Ltd. Methods for treating juvenile idiopathic arthritis
CA2693771A1 (en) * 2007-07-13 2009-01-22 Abbott Biotechnology Ltd. Methods and compositions for pulmonary administration of a tnf.alpha. inhibitor
JP2010535771A (ja) 2007-08-08 2010-11-25 アボット・ラボラトリーズ 抗体を結晶化させるための組成物及び方法
NZ602498A (en) 2007-11-30 2014-08-29 Abbvie Inc Protein formulations and methods of making same
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
US8986696B2 (en) 2007-12-21 2015-03-24 Depuy Mitek, Inc. Trans-capsular administration of p38 map kinase inhibitors into orthopedic joints
EP3575317A1 (de) 2007-12-26 2019-12-04 Xencor, Inc. Fc-varianten mit veränderter bindung zu fcrn
US20090271164A1 (en) * 2008-01-03 2009-10-29 Peng Joanna Z Predicting long-term efficacy of a compound in the treatment of psoriasis
KR20100120289A (ko) 2008-01-15 2010-11-15 애보트 게엠베하 운트 콤파니 카게 분말상 단백질 조성물 및 이의 제조 방법
EP2271671A2 (de) * 2008-03-24 2011-01-12 Abbott Biotechnology Ltd. Tnf-alpha-inhibitoren zur behandlung von knochenverlust
USRE48948E1 (en) 2008-04-18 2022-03-01 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable polymer
US20100239632A1 (en) 2009-03-23 2010-09-23 Warsaw Orthopedic, Inc. Drug depots for treatment of pain and inflammation in sinus and nasal cavities or cardiac tissue
US8722860B2 (en) 2009-04-16 2014-05-13 Abbvie Biotherapeutics Inc. Anti-TNF-α antibodies and their uses
KR101721906B1 (ko) 2009-04-29 2017-03-31 애브비 바이오테크놀로지 리미티드 자동 주입 장치
EP2512558A4 (de) 2009-12-15 2014-08-13 Abbvie Biotechnology Ltd Verbesserter auslöseknopf für automatische injektionsvorrichtung
AU2010330907A1 (en) * 2009-12-16 2012-06-14 Bosch, Phillip Methods of treating interstitial cystitis
JO3417B1 (ar) 2010-01-08 2019-10-20 Regeneron Pharma الصيغ المستقرة التي تحتوي على الأجسام المضادة لمضاد مستقبل( interleukin-6 (il-6r
CA2789168A1 (en) 2010-02-02 2011-08-11 Abbott Biotechnology Ltd. Methods and compositions for predicting responsiveness to treatment with tnf-.alpha. inhibitor
KR101850687B1 (ko) 2010-04-21 2018-04-20 애브비 바이오테크놀로지 리미티드 치료제의 제어된 전달을 위한 착용형 자동 주사 디바이스
WO2011146727A1 (en) 2010-05-19 2011-11-24 Philip Bosch Methods of treating interstitial cystitis
CN103079594B (zh) 2010-06-03 2016-04-13 艾伯维生物技术有限公司 用于治疗化脓性汗腺炎(hs)的用途和组合物
UY33679A (es) 2010-10-22 2012-03-30 Esbatech Anticuerpos estables y solubles
TWI603739B (zh) 2010-11-11 2017-11-01 艾伯維生物技術有限責任公司 具有增進高濃度之抗－ＴＮＦα抗體之液體調配物
EP4245219A3 (de) 2011-01-24 2023-11-01 AbbVie Biotechnology Ltd. Automatische injektionsvorrichtungen mit umspritzten greifflächen
EP2702077A2 (de) 2011-04-27 2014-03-05 AbbVie Inc. Verfahren zur steuerung des galactosylierungsprofil von rekombinant exprimierten proteinen
KR102014512B1 (ko) * 2011-05-02 2019-08-26 밀레니엄 파머슈티컬스 인코퍼레이티드 항-α4β7 항체에 대한 제형
WO2012174001A1 (en) 2011-06-13 2012-12-20 Abgenomics Cooperatief U.A. Anti-psgl-1 antibodies and uses thereof
EP2786156A2 (de) 2011-11-30 2014-10-08 AbbVie Deutschland GmbH & Co KG Verfahren und zusammensetzungen zur bestimmung des ansprechens auf eine behandlung mit einem tnf-alpha-hemmer
US9334319B2 (en) 2012-04-20 2016-05-10 Abbvie Inc. Low acidic species compositions
US9067990B2 (en) 2013-03-14 2015-06-30 Abbvie, Inc. Protein purification using displacement chromatography
US9181572B2 (en) 2012-04-20 2015-11-10 Abbvie, Inc. Methods to modulate lysine variant distribution
US9249182B2 (en) 2012-05-24 2016-02-02 Abbvie, Inc. Purification of antibodies using hydrophobic interaction chromatography
US9512214B2 (en) 2012-09-02 2016-12-06 Abbvie, Inc. Methods to control protein heterogeneity
KR20150043523A (ko) 2012-09-02 2015-04-22 애브비 인코포레이티드 단백질 불균일성의 제어 방법
KR102238677B1 (ko) 2012-09-07 2021-04-12 코히러스 바이오사이언시즈, 인코포레이티드 아달리무맙의 안정한 수성 제형
SG11201507230PA (en) 2013-03-12 2015-10-29 Abbvie Inc Human antibodies that bind human tnf-alpha and methods of preparing the same
US9499614B2 (en) 2013-03-14 2016-11-22 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides
US8921526B2 (en) 2013-03-14 2014-12-30 Abbvie, Inc. Mutated anti-TNFα antibodies and methods of their use
US9017687B1 (en) 2013-10-18 2015-04-28 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
US9598667B2 (en) 2013-10-04 2017-03-21 Abbvie Inc. Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins
US9181337B2 (en) 2013-10-18 2015-11-10 Abbvie, Inc. Modulated lysine variant species compositions and methods for producing and using the same
US8946395B1 (en) 2013-10-18 2015-02-03 Abbvie Inc. Purification of proteins using hydrophobic interaction chromatography
US9085618B2 (en) 2013-10-18 2015-07-21 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US20150139988A1 (en) 2013-11-15 2015-05-21 Abbvie, Inc. Glycoengineered binding protein compositions
US9763992B2 (en) 2014-02-13 2017-09-19 Father Flanagan's Boys' Home Treatment of noise induced hearing loss
GB201407852D0 (en) * 2014-05-02 2014-06-18 Iontas Ltd Preparation of libraries od protein variants expressed in eukaryotic cells and use for selecting binding molecules
US10689460B2 (en) 2014-05-15 2020-06-23 Incube Labs, Llc PCSK9 antibody preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10227403B2 (en) 2014-05-15 2019-03-12 Incube Labs, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising polypeptides and/or proteins
US10220076B2 (en) 2014-05-15 2019-03-05 Incube Labs, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising glucose regulating proteins
US11548940B2 (en) 2014-05-15 2023-01-10 Rani Therapeutics, Llc Anti-interleukin antibody preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US20170183376A1 (en) 2014-06-24 2017-06-29 Insight Biopharmaceuticals Ltd. Methods of purifying antibodies
CN104382977A (zh) * 2014-11-17 2015-03-04 昆明朗盛生物科技有限公司 一种女性专用的玛咖组合物
WO2016103093A1 (en) 2014-12-23 2016-06-30 Pfizer Inc. Stable aqueous antibody formulation for anti tnf alpha antibodies
EP3247718B1 (de) 2015-01-21 2021-09-01 Outlook Therapeutics, Inc. Modulation von ladungsvarianten in einer monoklonalen antikörperzusammensetzung
EP3078675A1 (de) 2015-04-10 2016-10-12 Ares Trading S.A. Induktionsdosierschema zur behandlung von krankheiten die von tnf alpha verursacht sind
US11229702B1 (en) 2015-10-28 2022-01-25 Coherus Biosciences, Inc. High concentration formulations of adalimumab
CA3004830A1 (en) 2015-11-11 2017-05-18 Opi Vi- Ip Holdco Llc Composition and methods for anti-tnfr2 antibodies
JP7084308B2 (ja) 2016-02-03 2022-06-14 アウトルック セラピューティクス，インコーポレイティド 抗体安定性を増大させるための緩衝液製剤
CA3016880A1 (en) * 2016-03-07 2017-09-14 Sanofi Biotechnology Compositions and methods for treating rheumatoid arthritis
US11071782B2 (en) 2016-04-20 2021-07-27 Coherus Biosciences, Inc. Method of filling a container with no headspace
KR20220119529A (ko) 2016-06-02 2022-08-29 애브비 인코포레이티드 글루코코르티코이드 수용체 작용제 및 이의 면역접합체
KR20190024572A (ko) * 2017-08-30 2019-03-08 (주)셀트리온 TNFα 관련 질환을 치료하기 위한 피하 투여 요법
EP3456739A1 (de) * 2017-09-19 2019-03-20 Tillotts Pharma Ag Verwendung von anti-tnfalpha antiköper in der behandlung von wunden
ES2877659T3 (es) 2017-12-01 2021-11-17 Abbvie Inc Agonista del receptor de glucocorticoides y sus inmunoconjugados
US11319375B2 (en) 2018-08-29 2022-05-03 Regeneron Pharmaceuticals, Inc. Methods and compositions for treating subjects having rheumatoid arthritis
CN114206442A (zh) 2019-01-31 2022-03-18 赛诺菲生物技术公司 用于治疗幼年特发性关节炎的抗il-6受体抗体
AR118191A1 (es) * 2019-02-28 2021-09-22 Celltrion Inc MÉTODOS PARA EL TRATAMIENTO DE ENFERMEDADES RELACIONADAS CON TNFa
CA3130348A1 (en) * 2019-03-14 2020-09-17 Motti HAKIM A method for immunosuppression
TW202128748A (zh) * 2020-01-24 2021-08-01 日商西斯美股份有限公司 提升抗體對抗原之親和性的方法及其用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998005357A1 (en) * 1996-08-01 1998-02-12 The Kennedy Institute Of Rheumatology Anti-tnf antibodies and methotrexate in the treatment of autoimmune disease
US6090382A (en) * 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα

Family Cites Families (121)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4399216A (en) 1980-02-25 1983-08-16 The Trustees Of Columbia University Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US5179017A (en) 1980-02-25 1993-01-12 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4634665A (en) 1980-02-25 1987-01-06 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
CA1208546A (en) 1981-09-08 1986-07-29 Anthony Cerami Lipoprotein lipase suppression by endotoxin-induced mediator (shock assay)
US4510245A (en) 1982-11-18 1985-04-09 Chiron Corporation Adenovirus promoter system
GB8308235D0 (en) 1983-03-25 1983-05-05 Celltech Ltd Polypeptides
US5672347A (en) 1984-07-05 1997-09-30 Genentech, Inc. Tumor necrosis factor antagonists and their use
IL73883A (en) 1984-12-20 1990-12-23 Yeda Res & Dev Monoclonal antibodies against tnf-alpha,hybridomas producing them and method for the purification of tnf-alpha
US5168062A (en) 1985-01-30 1992-12-01 University Of Iowa Research Foundation Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence
EP0212489B1 (de) 1985-08-16 1994-11-30 The Rockefeller University Modulator der anabolischen Aktivität und seine Verwendungen
US4870163A (en) 1985-08-29 1989-09-26 New York Blood Center, Inc. Preparation of pure human tumor necrosis factor and hybridomas producing monoclonal antibodies to human tumor necrosis factor
US5246714A (en) 1985-10-11 1993-09-21 Aktiebolaget Hassle Drug preparation
GB8528234D0 (en) 1985-11-15 1985-12-18 Wyeth John & Brother Ltd Heterocyclic compounds
US4968615A (en) 1985-12-18 1990-11-06 Ciba-Geigy Corporation Deoxyribonucleic acid segment from a virus
EP0230574A3 (de) 1986-01-31 1989-03-22 Yale University Pharmazeutische Zusammensetzungen gegen durch LAV/HTLV-III-Virus verursachte Infektionen und ihre Verwendung
DE3631229A1 (de) 1986-09-13 1988-03-24 Basf Ag Monoklonale antikoerper gegen humanen tumornekrosefaktor (tnf) und deren verwendung
JP2638652B2 (ja) 1988-07-18 1997-08-06 カイロン・コーポレーション カケクチンと反応するモノクロナール抗体
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
DE68914244T2 (de) 1988-10-24 1994-10-27 Otsuka Pharma Co Ltd Monoklonaler Antikörper.
DE68927671T2 (de) 1988-12-19 1997-05-07 American Cyanamid Co Produkte zur Behandlung des Endotoxin -Schocks bei einem Säugetier
WO1991002078A1 (en) 1989-08-07 1991-02-21 Peptide Technology Ltd Tumour necrosis factor binding ligands
FR2651130B1 (fr) 1989-08-23 1991-12-13 Roussel Uclaf Sequence d'oligonucleotides anti-sens, anti-arn message du tnf alpha, procede de preparation, application a titre de medicaments et compositions pharmaceutiques.
GB8921123D0 (en) 1989-09-19 1989-11-08 Millar Ann B Treatment of ards
GB8928874D0 (en) 1989-12-21 1990-02-28 Celltech Ltd Humanised antibodies
US5859205A (en) 1989-12-21 1999-01-12 Celltech Limited Humanised antibodies
US6075181A (en) * 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5945098A (en) 1990-02-01 1999-08-31 Baxter International Inc. Stable intravenously-administrable immune globulin preparation
DE4037604A1 (de) 1990-04-25 1991-10-31 Bayer Ag Verwendung von anti-tnf-antikoerpern als arzneimittel bei der behandlung von ischaemien und deren folgen
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
GB9014932D0 (en) 1990-07-05 1990-08-22 Celltech Ltd Recombinant dna product and method
GB9015198D0 (en) 1990-07-10 1990-08-29 Brien Caroline J O Binding substance
DK0585287T3 (da) 1990-07-10 2000-04-17 Cambridge Antibody Tech Fremgangsmåde til fremstilling af specifikke bindingsparelementer
CA2090401A1 (en) 1990-08-27 1992-02-28 Deborah A. Rathjen Method of treating viral infection
CA2405246A1 (en) 1990-12-03 1992-06-11 Genentech, Inc. Enrichment method for variant proteins with alterred binding properties
GB2279077B (en) 1990-12-21 1995-06-14 Celltech Ltd Therapeutic compositions comprising recombinant antibodies specific for the TNFalpha
GB9109645D0 (en) 1991-05-03 1991-06-26 Celltech Ltd Recombinant antibodies
US5994510A (en) 1990-12-21 1999-11-30 Celltech Therapeutics Limited Recombinant antibodies specific for TNFα
GB9028123D0 (en) 1990-12-28 1991-02-13 Erba Carlo Spa Monoclonal antibodies against human tumor necrosis factor alpha
ES2330052T3 (es) 1991-03-01 2009-12-03 Dyax Corporation Proteina quimerica que comprende micro-proteinas que tienen dos o mas puentes disulfuro y relaizaciones de las mismas.
JP3693671B2 (ja) 1991-03-15 2005-09-07 アムゲン インコーポレーテッド ポリペプチドのｐｅｇ化
US20070298040A1 (en) 1991-03-18 2007-12-27 Centocor, Inc. Methods of treating seronegative arthropathy with anti-TNF antibodies
US20040120952A1 (en) 2000-08-07 2004-06-24 Centocor, Inc Anti-TNF antibodies and peptides of human tumor necrosis factor
US5698195A (en) 1991-03-18 1997-12-16 New York University Medical Center Methods of treating rheumatoid arthritis using chimeric anti-TNF antibodies
DK0610201T4 (da) 1991-03-18 2008-02-04 Centocor Inc Monoklonale og kimære antistoffer, der er specifikke for human tumornekrosefaktor
US6277969B1 (en) 1991-03-18 2001-08-21 New York University Anti-TNF antibodies and peptides of human tumor necrosis factor
US20060246073A1 (en) 1991-03-18 2006-11-02 Knight David M Anti-TNF antibodies and peptides of human tumor necrosis factor
EP0604418B1 (de) 1991-03-29 1998-09-23 Immunex Corporation Isolierte virale proteine als cytokinantagonisten
DE69233750D1 (de) 1991-04-10 2009-01-02 Scripps Research Inst Bibliotheken heterodimerer Rezeptoren mittels Phagemiden
CA2103059C (en) * 1991-06-14 2005-03-22 Paul J. Carter Method for making humanized antibodies
DE4122599C2 (de) 1991-07-08 1993-11-11 Deutsches Krebsforsch Phagemid zum Screenen von Antikörpern
WO1993006213A1 (en) 1991-09-23 1993-04-01 Medical Research Council Production of chimeric antibodies - a combinatorial approach
WO1993011793A1 (en) 1991-12-17 1993-06-24 Schering Corporation Use of the combination of anti-tumor necrosis factor plus interleukin-6 to treat septic shock
US5195967A (en) * 1992-02-18 1993-03-23 Nakao Naomi L Anticlotting device and method for use with IV catheters
US5605923A (en) 1992-04-02 1997-02-25 Smithkline Beecham Corporation Compounds useful for treating inflammatory diseases and inhibiting production of tumor necrosis factor
DE69321909T2 (de) 1992-08-28 1999-04-01 Bayer Ag Verwendung von monoklonalen Anti-TNF-Antikörpern für die Behandlung von bakteriellen Meningitiden
CA2123593C (en) 1992-09-15 2000-03-14 Craig A. Smith Method of treating tnf-dependent inflammation using tumor necrosis factor antagonists
CA2147180A1 (en) 1992-10-15 1994-04-28 Gokhan S. Hotamisligil Treatment of insulin resistance in obesity linked type ii diabetes using antagonists to tnf-.alpha. function
DE122009000074I1 (de) 1993-03-05 2011-12-01 Bayer Healthcare Ag Humane monoklonale anti-TNF alpha Antikorper.
DE4307508A1 (de) 1993-03-10 1994-09-15 Knoll Ag Verwendung von anti-TNF-Antikörpern als Arzneimittel bei der Behandlung von Herzinsuffizienz (Herzmuskelschwäche)
CA2163032C (en) 1993-06-03 2001-02-06 John Landon Antibody fragments in therapy
US5500227A (en) 1993-11-23 1996-03-19 Euro-Celtique, S.A. Immediate release tablet cores of insoluble drugs having sustained-release coating
EP0659766A1 (de) 1993-11-23 1995-06-28 Schering-Plough Menschliche Monoklonalantikörper gegen menschliche Cytokine und Verfahren zur Herstellung dieser Antikörper
NZ278607A (en) 1994-02-07 1999-05-28 Knoll Ag Use of tnf antagonists for treating disorders involving elevated serum levels of il-6 wherein the serum levels are 500pg/ml or above
WO1995023813A1 (en) 1994-03-04 1995-09-08 Merck & Co., Inc. In vitro antibody affinity maturation using alanine scanning mutagenesis
ZA955642B (en) 1994-07-07 1997-05-06 Ortho Pharma Corp Lyophilized imaging agent formulation
PT1516628E (pt) 1995-07-27 2013-09-24 Genentech Inc Formulação de proteína liofilizada isotónica estável
US6267958B1 (en) * 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
HU228630B1 (en) 1996-02-09 2013-04-29 Abbott Biotech Ltd Use of human anti bodies that bind human tnf-alpha and process for inhibiting of human tnf-alpha activity
GB9610992D0 (en) * 1996-05-24 1996-07-31 Glaxo Group Ltd Concentrated antibody preparation
JP2000516594A (ja) 1996-07-26 2000-12-12 スミスクライン・ビーチャム・コーポレイション 免疫細胞介在全身性疾患の改良された治療法
US6171586B1 (en) 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
EP0999853B1 (de) 1997-06-13 2003-01-02 Genentech, Inc. Stabilisierte antikörperformulierung
US5971953A (en) * 1998-01-09 1999-10-26 Bachynsky; Nicholas Dual chamber syringe apparatus
DE69924375T2 (de) 1998-06-15 2005-08-11 Sepracor Inc. Verwendung von optisch reinem (+)-norcisapride für die behandlung des reizdarmsyndroms
JP3889197B2 (ja) * 1999-02-22 2007-03-07 中外製薬株式会社 プランジャロッド付きシリンジ製剤の製造方法及びその組付装置
US6419944B2 (en) 1999-02-24 2002-07-16 Edward L. Tobinick Cytokine antagonists for the treatment of localized disorders
US6423321B2 (en) 1999-02-24 2002-07-23 Edward L. Tobinick Cytokine antagonists for the treatment of sensorineural hearing loss
US6537549B2 (en) 1999-02-24 2003-03-25 Edward L. Tobinick Cytokine antagonists for the treatment of localized disorders
US6015557A (en) 1999-02-24 2000-01-18 Tobinick; Edward L. Tumor necrosis factor antagonists for the treatment of neurological disorders
PT1159003E (pt) 1999-03-02 2011-02-22 Centocor Inc Anti-tnf alfa na terapêutica da asma resistente a esteróides
PT1041072E (pt) * 1999-03-31 2003-11-28 Pfizer Prod Inc Acidos dioxociclopentil hidroxamicos
SE9901366D0 (sv) * 1999-04-16 1999-04-16 Pharmacia & Upjohn Ab Injector device and method for its operation
WO2000066160A1 (fr) 1999-04-28 2000-11-09 Yamanouchi Pharmaceutical Co., Ltd. Composition medicamenteuse parenterale a fragment d'anticorps monoclonal humanise et procede de stabilisation
US6502867B2 (en) 1999-06-16 2003-01-07 United States Pipe & Foundry Flanged pipe fitting
JP2003503360A (ja) 1999-06-24 2003-01-28 ファルマシア コーポレイション 炎症性疾患の処置のための併用療法
ATE389414T1 (de) * 1999-09-08 2008-04-15 Chugai Pharmaceutical Co Ltd Stabile proteinlösung abgefüllt in einem behältnis aus hydrophobem harz und eine methode zur stabilisierung derselben
WO2001037874A2 (en) 1999-11-24 2001-05-31 Centocor, Inc. Treatment of psoriasis by using an antibody to tnf alpha
US20030124119A1 (en) 1999-12-28 2003-07-03 Tadao Yamazaki Stable antibody compositions and injection preparations
GB0013810D0 (en) 2000-06-06 2000-07-26 Celltech Chiroscience Ltd Biological products
US20060018907A1 (en) 2000-08-07 2006-01-26 Centocor, Inc. Anti-TNF antibodies and peptides of human tumor necrosis factor
US20050249735A1 (en) 2000-08-07 2005-11-10 Centocor, Inc. Methods of treating ankylosing spondylitis using anti-TNF antibodies and peptides of human tumor necrosis factor
UA81743C2 (uk) 2000-08-07 2008-02-11 Центокор, Инк. МОНОКЛОНАЛЬНЕ АНТИТІЛО ЛЮДИНИ, ЩО СПЕЦИФІЧНО ЗВ'ЯЗУЄТЬСЯ З ФАКТОРОМ НЕКРОЗУ ПУХЛИН АЛЬФА (ФНПα), ФАРМАЦЕВТИЧНА КОМПОЗИЦІЯ, ЩО ЙОГО МІСТИТЬ, ТА СПОСІБ ЛІКУВАННЯ РЕВМАТОЇДНОГО АРТРИТУ
WO2002096461A1 (en) 2001-05-25 2002-12-05 Abbott Gmbh & Co. Kg Use of anti-tnf antibodies as drugs in treating septic disorders of anemic patients
CA2868614A1 (en) 2001-06-08 2002-12-08 Abbott Laboratories (Bermuda) Ltd. Methods of administering anti-tnf.alpha. antibodies
SI1425389T1 (sl) * 2001-08-23 2012-02-29 Genmab As Humana protitelesa, specifična za interlevkin 15 (IL-15)
US20030161828A1 (en) 2002-02-19 2003-08-28 Abbott Gmbh & Co. Kg Use of TNF antagonists as drugs for the treatment of patients with an inflammatory reaction and without suffering from total organ failure
WO2003080672A1 (en) 2002-03-22 2003-10-02 Aprogen, Inc. Humanized antibody and process for preparing same
US20040009172A1 (en) 2002-04-26 2004-01-15 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
MXPA05000815A (es) 2002-07-19 2005-04-28 Abbott Biotech Ltd Tratamiento de trastornos relacionados con tnfa.
US20090280065A1 (en) 2006-04-10 2009-11-12 Willian Mary K Uses and Compositions for Treatment of Psoriasis
US7226426B2 (en) 2002-07-25 2007-06-05 Thomson Paul E Apparatus and method for the detection and quantification of joint and tissue inflammation
US20040033228A1 (en) 2002-08-16 2004-02-19 Hans-Juergen Krause Formulation of human antibodies for treating TNF-alpha associated disorders
MY150740A (en) 2002-10-24 2014-02-28 Abbvie Biotechnology Ltd Low dose methods for treating disorders in which tnf? activity is detrimental
TW201705980A (zh) 2004-04-09 2017-02-16 艾伯維生物技術有限責任公司 用於治療ＴＮＦα相關失調症之多重可變劑量療法
WO2006041970A2 (en) 2004-10-08 2006-04-20 Abbott Biotechnology Ltd. Treatment of respiratory syncytial virus (rsv) infection
CN102961746B (zh) 2005-05-16 2016-06-15 艾伯维生物技术有限公司 TNFα抑制剂治疗腐蚀性多关节炎的用途
US20070041905A1 (en) 2005-08-19 2007-02-22 Hoffman Rebecca S Method of treating depression using a TNF-alpha antibody
BRPI0618085A2 (pt) 2005-11-01 2011-08-16 Abbott Biotech Ltd processos e kits para diagnóstico de espondilite ancilosante usando biomarcadores
CA2911000A1 (en) 2006-04-05 2007-10-18 Min W. Wan Antibody purification
US9605064B2 (en) 2006-04-10 2017-03-28 Abbvie Biotechnology Ltd Methods and compositions for treatment of skin disorders
JP5535623B2 (ja) 2006-06-30 2014-07-02 アッヴィ バイオテクノロジー リミテッド 自動注射装置
EP2089428B1 (de) 2006-10-27 2013-11-20 AbbVie Biotechnology Ltd Kristalline anti-htnfalpha-antikörper
JP2010535771A (ja) 2007-08-08 2010-11-25 アボット・ラボラトリーズ 抗体を結晶化させるための組成物及び方法
WO2014152463A1 (en) 2013-03-15 2014-09-25 Cyberheart, Inc. Apparatus and method for real-time tracking of tissue structures
KR101721906B1 (ko) 2009-04-29 2017-03-31 애브비 바이오테크놀로지 리미티드 자동 주입 장치
CA2760185A1 (en) 2009-05-04 2010-11-11 Abbott Biotechnology Ltd. Stable high protein concentration formulations of human anti-tnf-alpha antibodies
CN102167741B (zh) 2010-02-25 2014-05-14 上海百迈博制药有限公司 一种全人源抗TNF-α单克隆抗体、其制备方法及用途
CN103079594B (zh) 2010-06-03 2016-04-13 艾伯维生物技术有限公司 用于治疗化脓性汗腺炎(hs)的用途和组合物
GB201112429D0 (en) 2011-07-19 2011-08-31 Glaxo Group Ltd Antigen-binding proteins with increased FcRn binding
JP6274421B2 (ja) 2013-03-22 2018-02-07 キヤノンメディカルシステムズ株式会社 超音波診断装置及びその制御プログラム
KR102197477B1 (ko) 2014-07-04 2020-12-31 주식회사 유풍 모자

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6090382A (en) * 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
WO1998005357A1 (en) * 1996-08-01 1998-02-12 The Kennedy Institute Of Rheumatology Anti-tnf antibodies and methotrexate in the treatment of autoimmune disease

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; December 2002 (2002-12), GOTO DAISUKE ET AL: "[Adalimumab]" XP002373310 Database accession no. NLM12510366 & NIPPON RINSHO. JAPANESE JOURNAL OF CLINICAL MEDICINE. DEC 2002, vol. 60, no. 12, December 2002 (2002-12), pages 2384-2389, ISSN: 0047-1852 *
EGAN L J ET AL: "A RANDOMIZED, SINGLE-BLIND, PHARMACOKINETIC AND DOSERESPONSE STUDY OF SUBCUTANEOUS METHOTREXATE, 15 AND 25 MG/WEEK, FOR REFRACTORY ULCERATIVE COLITIS AND CROHN'S DISEASE" GASTROENTEROLOGY, SAUNDERS, PHILADELPHIA, PA,, US, vol. 114, no. 4, PART 2, 15 April 1998 (1998-04-15), page A970, XP009010308 ISSN: 0016-5085 *
Janeway C.A., Travers P., Walport M., Shlomchik M. J.: "Immunobiology 5", 2001, Garland Publishing, New York ISBN: 0821533642 page Ch. 3-6, *
KEMPENI J: "Preliminary results of early clinical trials with the fully human anti-TNFalpha monoclonal antibody D2E7" ANNALS OF THE RHEUMATIC DISEASES, BRITISH MEDICAL ASSOCIATION, LONDON, GB, vol. 58, no. 3, 1999, pages I70-I72, XP002979958 ISSN: 0003-4967 *
KEMPENI J: "UPDATE ON D2E7: A FULLY HUMAN ANTI-TUMOUR NECROSIS FACTOR ALPHA MONOCLONAL ANTIBODY" ANNALS OF THE RHEUMATIC DISEASES, BRITISH MEDICAL ASSOCIATION, LONDON, GB, vol. 59, no. SUPPL 1, November 2000 (2000-11), pages I44-I45, XP008061368 ISSN: 0003-4967 *
RAJPAL A ET AL: "A general method for greatly improving the affinity of antibodies by using combinatorial libraries", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES (PNAS), NATIONAL ACADEMY OF SCIENCE, US, vol. 102, no. 24, 1 June 2005 (2005-06-01) , pages 8466-8471, XP002392777, ISSN: 0027-8424, DOI: DOI:10.1073/PNAS.0503543102 *
RAU R ET AL: "ERFAHRUNGEN MIT D2E7 EXPERIENCES WITH D2E7" AKTUELLE RHEUMATOLOGIE, THIEME MED. PUBL., NEW YORK, NY,, US, vol. 25, no. 3, 2000, pages 83-88, XP008061373 ISSN: 0341-051X *
RAU R ET AL: "LONG-TERM TREATMENT WITH THE FULLY HUMAN ANTI-TNF-ANTIBODY D2E7 SLOWS RADIO-GRAPHIC DISEASE PROGRESSION IN RHEUMATOID ARTHRITIS" ARTHRITIS AND RHEUMATISM, LIPPINCOTT, PHILADELPHIA, US, vol. 42, no. 9, SUPPL, September 1999 (1999-09), page S400, XP009030226 ISSN: 0004-3591 *
SCHATTENKIRCHNER ET AL.: "LONG-TERM USE OF THE FULLY HUMAN ANTI-TNF ANTIBODY D2E7 IN COMBINATION WITH METHOTREXATE IN ACTIVE RHEUMATOID ARTHRITIS", ARTHRITIS & RHEUMATISM, vol. 43, no. Suppl.9, 968, September 2000 (2000-09), page S228, *
SCHATTENKIRCHNER M ET AL: "EFFICACY AND TOLERABILITY OF WEEKLY SUBCUTANEOUS INJECTIONS OF THE FULLY HUMAN ANTI-TNF-ANTIBODY D2E7 IN PATIENTS WITH RHEUMATOID ARTHRITIS - RESULTS OF A PHASE I STUDY" ARTHRITIS AND RHEUMATISM, LIPPINCOTT, PHILADELPHIA, US, vol. 41, no. 9, SUPPL, 12 November 1998 (1998-11-12), page S57, XP008061372 ISSN: 0004-3591 *
See also references of WO02100330A2 *
SIGMA ALDRICH CO.: '85011425 L929 Cell Line from mouse', [Online] 12 July 2007, Sigma Online Catalog Retrieved from the Internet: <URL:http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIGMA/85011425> [retrieved on 2007-07-12] *
VAN DE PUTTE L B A ET AL: "Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed", ANNALS OF THE RHEUMATIC DISEASES, BRITISH MEDICAL ASSOCIATION, LONDON, GB, vol. 63, no. 5, 1 May 2004 (2004-05-01), pages 508-516, XP002632098, ISSN: 0003-4967, DOI: 10.1136/ARD.2003.013052 *
VAN DE PUTTE L B A ET AL: "Efficacy of the fully human anti-TNF antibody D2E7 in rheumatoid arthritis" ARTHRITIS AND RHEUMATISM, vol. 42, no. 9 SUPPL., September 1999 (1999-09), page S400, XP002373254 & 63RD ANNUAL SCIENTIFIC MEETING OF THE AMERICAN COLLEGE OF RHEUMATOLOGY AND THE 34TH ANNUAL SCIENTIFI; BOSTON, MASSACHUSETTS, USA; NOVEMBER 13-17, 1999 ISSN: 0004-3591 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8992926B2 (en) 2001-06-08 2015-03-31 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
EP2940044B1 (de) 2001-06-08 2016-11-16 AbbVie Biotechnology Ltd Anti-tnf-alpha-antikörpern zur verwendung in therapie
US10376582B2 (en) 2013-10-16 2019-08-13 Outlook Therapeutics, Inc. Buffer formulations for enhanced antibody stability
US10653747B2 (en) 2014-07-31 2020-05-19 Uab Research Foundation ApoE mimetic peptides and higher potency to clear plasma cholesterol

Also Published As

Publication number Publication date
US20150175691A1 (en) 2015-06-25
KR20100075698A (ko) 2010-07-02
US8992926B2 (en) 2015-03-31
US9073987B2 (en) 2015-07-07
SI2940044T1 (sl) 2017-03-31
PT1406656E (pt) 2013-03-25
EP2324851A1 (de) 2011-05-25
US20150023982A1 (en) 2015-01-22
KR20140012210A (ko) 2014-01-29
KR101497363B1 (ko) 2015-03-03
TW201332570A (zh) 2013-08-16
BG66936B1 (bg) 2019-08-15
NO20035426D0 (no) 2003-12-05
BG66459B1 (bg) 2014-10-31
CN105412922A (zh) 2016-03-23
JP2012184242A (ja) 2012-09-27
BG108514A (en) 2005-04-30
PL217702B1 (pl) 2014-08-29
IL222495A (en) 2015-03-31
US20150071945A1 (en) 2015-03-12
NZ586063A (en) 2012-02-24
PH12013500866A1 (en) 2016-02-22
HUP0600688A2 (en) 2006-11-28
KR20120139851A (ko) 2012-12-27
PL366694A1 (en) 2005-02-07
IL158831A (en) 2014-06-30
TWI473622B (zh) 2015-02-21
MXPA03011316A (es) 2004-12-06
SK16462003A3 (sk) 2004-08-03
US20140271637A1 (en) 2014-09-18
CY1120540T1 (el) 2019-07-10
CN101574520A (zh) 2009-11-11
JP2009167193A (ja) 2009-07-30
EP1406656B1 (de) 2013-01-09
EP2940044B8 (de) 2017-01-18
WO2002100330A9 (en) 2007-06-21
IL158831A0 (en) 2004-05-12
NZ529574A (en) 2006-05-26
EP2364731A9 (de) 2012-06-20
KR20160096222A (ko) 2016-08-12
NO20035426L (no) 2004-02-03
CA2868614A1 (en) 2002-12-08
KR101715028B1 (ko) 2017-03-10
KR101282807B1 (ko) 2013-07-05
EP2359855A2 (de) 2011-08-24
JP5832952B2 (ja) 2015-12-16
PH12013500865B1 (en) 2016-02-01
PL215861B1 (pl) 2014-02-28
HK1065471A1 (en) 2005-02-25
JP2015003922A (ja) 2015-01-08
JP2013100311A (ja) 2013-05-23
NZ573478A (en) 2011-02-25
PL399548A1 (pl) 2012-11-05
US20160280777A1 (en) 2016-09-29
US20150165023A1 (en) 2015-06-18
JP2005517629A (ja) 2005-06-16
CN1638796A (zh) 2005-07-13
HUP0600688A3 (en) 2012-09-28
ES2612436T3 (es) 2017-05-16
MX341001B (es) 2016-08-03
CA2817619A1 (en) 2002-12-08
NO343721B1 (no) 2019-05-20
EP2359855A3 (de) 2011-11-02
NZ596878A (en) 2013-07-26
JP2017031213A (ja) 2017-02-09
EP2940044A1 (de) 2015-11-04
CN103495165A (zh) 2014-01-08
PL217217B1 (pl) 2014-06-30
JP2015166389A (ja) 2015-09-24
PT2940044T (pt) 2017-01-12
DK2940044T3 (en) 2017-02-20
US20150017175A1 (en) 2015-01-15
JP6074462B2 (ja) 2017-02-01
CA2385745C (en) 2015-02-17
NZ560792A (en) 2009-09-25
PL394085A1 (pl) 2011-07-04
ES2400458T3 (es) 2013-04-10
US9017680B2 (en) 2015-04-28
NO334490B1 (no) 2014-03-17
US8974790B2 (en) 2015-03-10
BG111719A (bg) 2014-06-30
SA02230384B1 (ar) 2009-08-19
EP2940044B1 (de) 2016-11-16
KR20090035746A (ko) 2009-04-10
ZA200308861B (en) 2004-09-13
SI1406656T1 (sl) 2013-04-30
NZ545649A (en) 2009-04-30
EP3190124A1 (de) 2017-07-12
US20130004507A1 (en) 2013-01-03
DK1406656T3 (da) 2013-04-15
KR20040030661A (ko) 2004-04-09
NO20120288L (no) 2004-02-03
US20150246968A1 (en) 2015-09-03
PH12013500866B1 (en) 2016-02-22
CN103110944A (zh) 2013-05-22
PL399491A1 (pl) 2012-10-08
CL2012000856A1 (es) 2012-09-14
EP2359855A9 (de) 2012-06-20
AU2002314922C1 (en) 2017-11-09
CZ309160B6 (cs) 2022-03-30
US20150071939A1 (en) 2015-03-12
CZ200420A3 (cs) 2005-01-12
PE20160999A1 (es) 2016-10-08
US20150079101A1 (en) 2015-03-19
US9546212B2 (en) 2017-01-17
US20030235585A1 (en) 2003-12-25
US8889135B2 (en) 2014-11-18
AU2002314922B2 (en) 2008-05-15
KR101142825B1 (ko) 2012-05-08
EP1406656A4 (de) 2006-05-24
PE20030065A1 (es) 2003-02-12
PL217666B1 (pl) 2014-08-29
IL212419A (en) 2015-03-31
ECSP034867A (es) 2004-01-28
EP2364731A3 (de) 2011-11-02
PH12013500297A1 (en) 2015-09-07
PH12013500865A1 (en) 2016-02-01
LT2940044T (lt) 2017-01-10
US20140186368A1 (en) 2014-07-03
AR034429A1 (es) 2004-02-25
SK288509B6 (sk) 2017-11-03
US20120177596A1 (en) 2012-07-12
CA2385745A1 (en) 2002-12-08
US20200181252A1 (en) 2020-06-11
KR20080089681A (ko) 2008-10-07
EP2364731A2 (de) 2011-09-14
JP6302529B2 (ja) 2018-03-28
IL212419A0 (en) 2011-06-30
BR0206289A (pt) 2004-11-30
AR077572A2 (es) 2011-09-07
WO2002100330A2 (en) 2002-12-19
HU230947B1 (hu) 2019-05-28
AR090099A2 (es) 2014-10-22
WO2002100330A3 (en) 2004-02-12
US8911737B2 (en) 2014-12-16
US20140322232A1 (en) 2014-10-30
KR20110039505A (ko) 2011-04-18

Similar Documents

Publication Publication Date Title
US20200181252A1 (en) Methods of administering anti-tnfalpha antibodies
AU2002314922A1 (en) Methods of administering anti-TNFalpha antibodies
AU2013204357B2 (en) Methods of administering anti-TNFalpha antibodies
AU2011218743B2 (en) Methods of administering anti-TNFalpha antibodies
AU2008202001B2 (en) Methods of administering anti-TNFalpha antibodies

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040108

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1065471

Country of ref document: HK

A4 Supplementary search report drawn up and despatched

Effective date: 20060412

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/519 20060101ALN20060401BHEP

Ipc: A61P 11/00 20060101ALI20060401BHEP

Ipc: A61K 39/395 20060101AFI20040226BHEP

Ipc: A61P 9/00 20060101ALI20060401BHEP

Ipc: A61P 37/00 20060101ALI20060401BHEP

Ipc: A61P 35/00 20060101ALI20060401BHEP

Ipc: A61P 17/02 20060101ALI20060401BHEP

Ipc: A61P 19/00 20060101ALI20060401BHEP

Ipc: C07K 16/00 20060101ALI20060401BHEP

Ipc: A61P 31/00 20060101ALI20060401BHEP

Ipc: A61K 31/519 20060101ALI20060401BHEP

Ipc: A61P 7/00 20060101ALI20060401BHEP

Ipc: A61P 1/16 20060101ALI20060401BHEP

Ipc: A61K 38/20 20060101ALI20060401BHEP

Ipc: A61P 29/00 20060101ALI20060401BHEP

Ipc: A61K 39/395 20060101ALN20060401BHEP

Ipc: A61P 1/00 20060101ALI20060401BHEP

Ipc: A61K 38/20 20060101ALN20060401BHEP

Ipc: C07K 16/24 20060101ALN20060401BHEP

Ipc: A61M 5/178 20060101ALI20060401BHEP

Ipc: A61P 41/00 20060101ALI20060401BHEP

17Q First examination report despatched

Effective date: 20070612

R17D Deferred search report published (corrected)

Effective date: 20070621

REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Ref document number: 60244379

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: A61K0039395000

Ipc: C07K0016240000

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 37/06 20060101ALI20120718BHEP

Ipc: A61K 39/395 20060101ALI20120718BHEP

Ipc: A61K 31/519 20060101ALN20120718BHEP

Ipc: A61P 19/02 20060101ALI20120718BHEP

Ipc: C07K 16/24 20060101AFI20120718BHEP

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 37/06 20060101ALI20120730BHEP

Ipc: A61K 39/395 20060101ALI20120730BHEP

Ipc: C07K 16/24 20060101AFI20120730BHEP

Ipc: A61P 19/02 20060101ALI20120730BHEP

Ipc: A61K 31/519 20060101ALN20120730BHEP

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ABBVIE BIOTECHNOLOGY LTD

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

Ref country code: AT

Ref legal event code: REF

Ref document number: 592712

Country of ref document: AT

Kind code of ref document: T

Effective date: 20130115

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 60244379

Country of ref document: DE

Effective date: 20130314

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20130314

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2400458

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20130410

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Ref country code: CH

Ref legal event code: NV

Representative=s name: BOHEST AG, CH

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20130400427

Country of ref document: GR

Effective date: 20130327

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

PLBI Opposition filed

Free format text: ORIGINAL CODE: 0009260

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1065471

Country of ref document: HK

PLBI Opposition filed

Free format text: ORIGINAL CODE: 0009260

26 Opposition filed

Opponent name: AMGEN INC.

Effective date: 20130829

PLBI Opposition filed

Free format text: ORIGINAL CODE: 0009260

PLBI Opposition filed

Free format text: ORIGINAL CODE: 0009260

26 Opposition filed

Opponent name: PFIZER INC.

Effective date: 20130926

26 Opposition filed

Opponent name: KILBURN & STRODE LLP

Effective date: 20131003

Opponent name: AET BIOTECHNOLOGIE GMBH

Effective date: 20131002

PLAX Notice of opposition and request to file observation + time limit sent

Free format text: ORIGINAL CODE: EPIDOSNOBS2

26 Opposition filed

Opponent name: APPELT, CHRISTIAN W.

Effective date: 20131009

Opponent name: STRAWMAN LIMITED

Effective date: 20131007

Opponent name: ZWICKER SCHNAPPAUF & PARTNER PATENTANWAELTE

Effective date: 20131008

Opponent name: HOFFMANN EITLE

Effective date: 20131009

Opponent name: GEDEON RICHTER PHARMA GMBH

Effective date: 20131007

Opponent name: SCHLICH, GEORGE

Effective date: 20131008

Opponent name: BREUER, MARKUS

Effective date: 20131008

Opponent name: BIRD, WILLIAM EDWARD

Effective date: 20131009

Opponent name: GENERICS (UK) LIMITED

Effective date: 20131007

Opponent name: WEISS, WOLFGANG

Effective date: 20131008

Opponent name: TEVA PHARMACEUTICAL INDUSTRIES LTD.

Effective date: 20131008

REG Reference to a national code

Ref country code: DE

Ref legal event code: R026

Ref document number: 60244379

Country of ref document: DE

Effective date: 20130829

PLAF Information modified related to communication of a notice of opposition and request to file observations + time limit

Free format text: ORIGINAL CODE: EPIDOSCOBS2

PLAB Opposition data, opponent's data or that of the opponent's representative modified

Free format text: ORIGINAL CODE: 0009299OPPO

R26 Opposition filed (corrected)

Opponent name: STRAWMAN LIMITED

Effective date: 20131007

PLAF Information modified related to communication of a notice of opposition and request to file observations + time limit

Free format text: ORIGINAL CODE: EPIDOSCOBS2

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCAR

Free format text: NEW ADDRESS: HOLBEINSTRASSE 36-38, 4051 BASEL (CH)

PLBB Reply of patent proprietor to notice(s) of opposition received

Free format text: ORIGINAL CODE: EPIDOSNOBS3

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 14

PLAB Opposition data, opponent's data or that of the opponent's representative modified

Free format text: ORIGINAL CODE: 0009299OPPO

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MC

Payment date: 20150528

Year of fee payment: 14

Ref country code: LU

Payment date: 20150604

Year of fee payment: 14

Ref country code: ES

Payment date: 20150609

Year of fee payment: 14

Ref country code: DK

Payment date: 20150527

Year of fee payment: 14

Ref country code: SE

Payment date: 20150605

Year of fee payment: 14

Ref country code: GB

Payment date: 20150526

Year of fee payment: 14

Ref country code: CH

Payment date: 20150428

Year of fee payment: 14

Ref country code: TR

Payment date: 20150520

Year of fee payment: 14

Ref country code: FI

Payment date: 20150609

Year of fee payment: 14

Ref country code: PT

Payment date: 20150527

Year of fee payment: 14

R26 Opposition filed (corrected)

Opponent name: TEVA PHARMACEUTICAL INDUSTRIES LTD.

Effective date: 20131008

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20150611

Year of fee payment: 14

Ref country code: AT

Payment date: 20150527

Year of fee payment: 14

Ref country code: IE

Payment date: 20150609

Year of fee payment: 14

Ref country code: GR

Payment date: 20150602

Year of fee payment: 14

Ref country code: FR

Payment date: 20150528

Year of fee payment: 14

Ref country code: BE

Payment date: 20150605

Year of fee payment: 14

Ref country code: NL

Payment date: 20150616

Year of fee payment: 14

PLAB Opposition data, opponent's data or that of the opponent's representative modified

Free format text: ORIGINAL CODE: 0009299OPPO

R26 Opposition filed (corrected)

Opponent name: STRAWMAN LIMITED

Effective date: 20131007

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20150630

Year of fee payment: 14

Ref country code: CY

Payment date: 20150522

Year of fee payment: 14

RDAF Communication despatched that patent is revoked

Free format text: ORIGINAL CODE: EPIDOSNREV1

REG Reference to a national code

Ref country code: DE

Ref legal event code: R064

Ref document number: 60244379

Country of ref document: DE

Ref country code: DE

Ref legal event code: R103

Ref document number: 60244379

Country of ref document: DE

REG Reference to a national code

Ref country code: GB

Ref legal event code: S72Z

Free format text: CLAIM LODGED; CLAIM FOR REVOCATION LODGED AT THE PATENTS COURT ON 29 OCTOBER 2015 (HP-2015-000053)

RDAG Patent revoked

Free format text: ORIGINAL CODE: 0009271

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: PATENT REVOKED

REG Reference to a national code

Ref country code: CH

Ref legal event code: PLX

27W Patent revoked

Effective date: 20151126

GBPR Gb: patent revoked under art. 102 of the ep convention designating the uk as contracting state

Effective date: 20151126

REG Reference to a national code

Ref country code: PT

Ref legal event code: MP4A

Effective date: 20160330

REG Reference to a national code

Ref country code: GB

Ref legal event code: S72Z

Free format text: PATENT REVOKED BY EPO ON 26 NOVEMBER 2015.

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF THE APPLICANT RENOUNCES

Effective date: 20130109

Ref country code: CH

Free format text: LAPSE BECAUSE OF THE APPLICANT RENOUNCES

Effective date: 20130109

REG Reference to a national code

Ref country code: AT

Ref legal event code: MA03

Ref document number: 592712

Country of ref document: AT

Kind code of ref document: T

Effective date: 20151126

Ref country code: GR

Ref legal event code: NF

Ref document number: 20130400427

Country of ref document: GR

Effective date: 20160505

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20170218

REG Reference to a national code

Ref country code: SE

Ref legal event code: ECNC